(2-((2-alkoxy)-phenyl)-cyclopent-1enyl) aromatic carbo and heterocyclic acid and derivatives

ABSTRACT

Compounds of formula (I) or a pharmaceutically acceptable derivative thereof:  
                 
 
wherein A, R 1 , R 2 , R x , R 8 , R 9  and n are as defined in the specification, a process for the preparation of such compounds, pharmaceutical compositions comprising such compounds and the use of such compounds in medicine.

This invention relates to cyclopentene compounds, to processes for theirpreparation, to pharmaceutical compositions containing them and to theiruse in medicine, in particular their use in the treatment ofprostaglandin mediated diseases.

The EP₁ receptor is a 7-transmembrane receptor and its natural ligand isthe prostaglandin PGE₂. PGE₂ also has affinity for the other EPreceptors (types EP₂, EP₃ and EP₄). The EP₁ receptor is associated withsmooth muscle contraction, pain (in particular inflammatory, neuropathicand visceral), inflammation, allergic activities, renal regulation andgastric or enteric mucus secretion. We have now found a novel group ofcompounds which bind with high affinity to the EP₁ receptor.

A number of review articles describe the characterization andtherapeutic relevance of the prostanoid receptors as well as the mostcommonly used selective agonists and antagonists: Eicosanoids; FromBiotechnology to Therapeutic Applications, Folco, Samuelsson, Maclouf,and Velo eds, Plenum Press, New York, 1996, chap. 14, 137-154 andJournal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87 andProstanoid Receptors, Structure, Properties and Function, S Narumiya etal, Physiological Reviews 1999, 79 (4), 1193-126. An article from TheBritish Journal of Pharmacology, 1994, 112, 735-740 suggests thatProstaglandin E₂ (PGE₂) exerts allodynia through th EP₁ receptor subtypeand hyperalgesia through EP₂ and EP₃ receptors in the mouse spinal corn.Furthermore an article from The Journal of Clinical Investigation, 2001,107 (3), 325 shows what in the EP₁ knock-out mouse pain-sensitivityresponses are reduced by approximately 50%. Two papers from Anesthesiaand Analgesia have shown that (2001, 93, 1012-7) an EP₁ receptorantagonist (ONO-8711) reduces hyperalgesia and allodynia in a rat modelof chronic constriction injury, and that (2001, 92, 233-238) the sameantagonist inhibits mechanical hyperalgesia in a rodent model ofpost-operative pain. S. Sarkar et al in Gastroenterology, 2003, 124 (1),18-25 demonstrate the efficacy of EP₁ receptor antagonists in thetreatment of visceral pain in a human model of hypersensitivity. Thus,selective prostaglandin ligands, agonists or antagonists, depending onwhich prostaglandin E receptor subtype is being considered, haveanti-inflammatory, antipyretic and analgesic properties similar to aconventional non-steroidal anti-inflammatory drug, and in addition,inhibit hormone-induced uterine contractions and have anti-cancereffects. These compounds have a diminished ability to induce some of themechanism-based side effects of NSAIDs which are indiscriminatecyclooxygenase inhibitors. In particular, the compounds have a reducedpotential for gastrointestinal toxicity, a reduced potential for renalside effects, a reduced effect on bleeding times and a lessened abilityto induce asthma attacks in aspirin-sensitive asthmatic subjects.Moreover, by sparing potentially beneficial prostaglandin pathways,these agents may have enhanced efficacy over NSAIDS and/or COX-2inhibitors.

In The American Physiological Society (1994, 267, R289R-294), studiessuggest that PGE₂-induced hyperthermia in the rat is mediatedpredominantly through the EP₁ receptor. WO 96/06822 (Mar. 7, 1996), WO96/11902 (Apr. 25, 1996), EP 752421-A1 (Jan. 8, 1997) and WO 01/19814(22 Mar. 2001) disclose compounds as being useful in the treatment ofprostaglandin mediated diseases.

Accordingly the present invention provides compounds of formula (I):

wherein:

-   A represents an optionally substituted phenyl, or an optionally    substituted 5- or 6-membered heterocyclyl ring, or an optionally    substituted bicyclic heterocyclyl group;-   R¹ represents CO₂R⁴, CONR⁵R⁶, CH₂CO₂R⁴, optionally substituted    alkyl, optionally substituted alkenyl, optionally substituted    SO₂alkyl, SO₂NR⁵R⁶, NR⁵CONR⁵R⁶, CONR⁵R⁶, 2H-tetrazol-5-yl-methyl or    optionally substituted heterocyclyl;-   R² independently represents halo, optionally substituted alkyl, CN,    SO₂R⁵, SR⁵, NO₂, optionally substituted aryl, CON R⁵R⁶ or optionally    substituted heteroaryl;-   R^(x) represents optionally substituted alkyl wherein 1 or 2 of the    non-terminal carbon atoms may optionally be replaced by a group    independently selected from NR⁴, O or SO_(n), wherein n is 0, 1 or    2: or R^(x) may be optionally substituted CQ₂-heterocyclyl or    optionally substituted CQ₂-phenyl wherein Q is independently    selected from hydrogen and CH₃ ⁻;-   R⁴ represents hydrogen or an optionally substituted alkyl;-   R⁵ represents hydrogen or an optionally substituted alkyl;-   R⁶ represents hydrogen or an optionally substituted alkyl,    optionally substituted SO₂aryl, optionally substituted    SO₂heterocyclyl group, CN, optionally substituted CH₂aryl or COR⁷;-   R⁷ represents hydrogen, optionally substituted heteroaryl or    optionally substituted aryl;-   R⁸ and R⁹ independently represent hydrogen or alkyl; and-   n is an integer from 0 to 2;    wherein when A is a 6-membered ring the R¹ and cyclopentene group    are attached to carbon atoms 1,2-, 1,3- or 1,4-relative to each    other, and when A is a five-membered ring or bicyclic heterocyclyl    group the R¹ and cyclopentene group are attached to substitutable    carbon atoms 1,2- or 1,3-relative to each other;    or pharmaceutically acceptable derivatives thereof.

When A is a six membered ring, preferably R¹ is attached to the group Ain the 3 position relative to the bond attaching A to the cyclopentenering.

Preferably R¹ represents CO₂R⁴, wherein R⁴ is hydrogen or C₁₋₄alkyl.

Preferably A is selected from phenyl, pyridyl, pyridazinyl, pyrazinyl orpyrimidinyl, all of which may be optionally substituted. In an otheraspect, A is selected from an optionally substituted phenyl, pyridyl,pyridazinyl, pyrazinyl or pyrimidinyl; more preferably A is pyridyl oran optionally substituted phenyl; most preferably A is optionallysubstituted phenyl. In an alternative aspect A is pyridyl.

In an alternative aspect:

-   A represents an optionally substituted phenyl, or an optionally    substituted 5 or 6-membered heterocyclyl group;-   R¹ represents CO₂R⁴, CONR⁵R⁶, CH₂CO₂R⁴, optionally substituted    C₁₋₆alkyl, optionally substituted C₁₋₆alkenyl, SO₂C₁₋₄alkyl,    SO₂NR⁵R⁶, NR⁵CONR⁵R⁶, tetrazolyl or CONR⁵R⁶;-   R² independently represents halo, optionally substituted C₁₋₆alkyl,    CN, SO₂R⁵, SR⁵, NO₂, optionally substituted aryl, CONR⁵R⁶ or    optionally substituted heteroaryl;-   R^(x) represents optionally substituted C₁₋₈alkyl or optionally    substituted —CH₂-Phenyl;-   R⁴ represents hydrogen or an optionally substituted C₁₋₆alkyl;-   R₅ represents hydrogen or an optionally substituted C₁₋₆alkyl;-   R⁶ represents hydrogen or an optionally substituted C₁₋₆alkyl,    optionally substituted-   SO₂aryl, optionally substituted SO₂heterocyclyl group, CN,    optionally substituted CH₂aryl or COR⁷;-   R⁷ represents hydrogen or an optionally substituted aryl;-   R⁸ and R⁹ independently represent hydrogen or C₁₋₆alkyl;-   n is an integer from 0 to 2;    wherein R¹ is attached to the group A in the 3 or 4 position    relative to the bond attaching A to the cyclopentene ring;    or pharmaceutically acceptable derivatives thereof.

In a further aspect, A is optionally substituted phenyl or a 5 or6-membered heterocyclyl group.

Optional substituents for A when a phenyl group include up to foursubstituents, preferably 0 or 1 substituent, independently selected fromhalogen, NR⁵R⁶, NR⁵COC₁₋₈alkyl, NR⁵SO₂C₁₋₆alkyl, OR⁵, C₁₋₆alkyl andNR¹⁰R¹¹ wherein R¹⁰ and R¹¹ together with the nitrogen atom to whichthey are attached form a morpholine ring, a 5- or 6-membered lactam ringor a 5- or 6-membered cyclic sulphonamide, wherein R⁵ and R⁶ are asdefined above. Preferably optional substituents for A are selected fromhalogen, NR⁵R⁶, NHCOC₁₋₆alkyl, NHSO₂C₁₋₆alkyl, C₁₋₆alkyl and NR¹⁰R¹¹.

In an alternative aspect optional substituents for A when a phenyl groupinclude up to four substituents independently selected from C₁₋₆alkyl,C₁₋₆alkoxy and halogen. Preferably A when a phenyl group is optionallysubstituted by up to 2 substituents.

Optional substituents for A when a 5- or 6-membered heterocyclyl groupinclude NH₂. When A is pyridyl it may be substitued on the ring nitrogenby an oxygen to give a pyridine N-oxide. In an alternative aspect R¹represents CO₂R⁴, CONR⁵R⁶, CH₂CO₂R⁴, optionally substituted C₁₋₆alkyl,optionally substituted C₁₋₆alkenyl, SO₂C₁₋₆alkyl, SO₂NR⁵R⁶, NR⁵CONR⁵R⁶,tetrazolyl or COSO₂NR⁵R⁶.

In another aspect R² independently represents halo, optionallysubstituted C₁₋₆-alkyl, CN, SO₂R⁵, NO₂, optionally substituted aryl,CONR⁵R⁶ or optionally substituted heteroaryl. In an alternative aspectR⁶ represents hydrogen or an optionally substituted C₁₋₆alkyl,optionally substituted SO₂aryl, optionally substituted SO₂heterocyclylgroup, CN, or COR⁷. Preferably R¹ represents CO₂R⁴. More preferably R¹represents CO₂H.

Preferably R² represents halo, optionally substituted C₁₋₆-alkyl e.g.C₁₋₄alkyl and CF₃, CN, SC₁₋₆alkyl, e.g SCH₃ or SO₂C₁₋₆alkyl, e.g.SO₂CH₃. Alternatively R² represents halogen, optionally substitutedC₁₋₆alkyl, for example CF₃, CN or SO₂C₁₋₆alkyl.

Preferably R⁴ represents hydrogen or C₁₋₃alkyl.

Preferably R⁵ represents hydrogen or C₁₋₃alkyl.

Preferably R⁶ represents hydrogen or C₁₋₃alkyl.

Preferably R⁸ represents methyl or hydrogen, more preferably R⁸represents hydrogen.

Preferably R⁹ represents hydrogen.

Preferably n is 0 or 1.

When R^(x) represents an optionally substituted alkyl this group ispreferably C₁₋₈alkyl, more preferably the alkyl group isCH₂C₅₋₆cycloalkyl.

R^(x) preferably represents CH₂phenyl optionally substituted by one, twoor three, preferably one or two substituents selected from Cl, Br, F,CF₃, C₁₋₄alkyl and OC₁₋₄alkyl or R^(x) is CH₂C₅₋₆cycloalkyl.

Preferred compounds of formula (I) are compounds of formula (II):

wherein:

-   R¹ is CO₂R⁴;-   R² is halo, optionally substituted C₁₋₆alkyl e.g. C₁₋₄alkyl and CF₃,    CN, SC₁₋₈alkyl, or SO₂C₁₋₆alkyl;-   R³ independently represents halo, optionally substituted OC₁₋₆alkyl,    or optionally substituted C₁₋₆alkyl;-   m is an integer from 0 to 3;-   n is an integer from 0 to 2;-   W, X, Y and Z each represents CR¹² or N wherein at least two of W,    X, Y or Z is CR¹²; and    when each of W, X, Y, and Z is CR¹² then each R¹² is independently    selected from hydrogen, halogen, NR⁵R⁶, NHCOC₁₋₆alkyl,    NHSO₂C₁₋₆alkyl, C₁₋₈alkyl and NR¹⁰R¹¹, and    when at least one of W, X, Y and Z represents N then each R¹² is    selected from hydrogen or NH₂;    or pharmaceutically acceptable derivatives thereof.

In an alternative aspect of compounds of formula II:

-   R¹ is CO₂R⁴;-   R² is halogen, optionally substituted C₁₋₆alkyl e.g. CF₃, CN,    SC₁₋₆alkyl or SO₂C₁₋₆alkyl;-   R³ independently represents halo or an optionally substituted    OC₁₋₆alkyl, or C₁₋₆alkyl;-   m is an integer from 0 to 2;-   n is an integer from 0 to 2;-   W, X, Y and Z represents CH or N wherein at least two of W, X, Y or    Z is CH;    or pharmaceutically acceptable derivatives thereof.

In another aspect R² is halogen, optionally substituted C₁₋₆alkyl e.g.CF₃, CN, or SO₂C₁₋₆alkyl.

In a further aspect R³ represents halo, optionally substituted C₁₋₄alkyle.g. CF₃, or optionally substituted OC₁₋₄alkyl, more preferably R³ ishalo or OMe.

-   Compounds of formula (I) include:-   {2-[5-chloro-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic acid;-   3-{2-[2-(benzyloxy)-phenyl]cyclopent-1-enyl]-benzoic acid;-   3-{2-[5-bromo-2-(benzyloxy)phenyl]-cyclopent-1-enyl}-benzoic acid;-   3-{2-[5-bromo-2-(4-Chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic    acid;-   3-{2-[5-bromo-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic    acid;-   3-{2-[5-bromo-2-(3,4-dichlorobenzyloxy)-penyl]-cyclopent-1-enyl}-benzoic    acid;-   3-{2-[5-bromo-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic    acid;-   3-{2-[5-bromo-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic    acid;-   3-{2-[5-bromo-2-(4-methoxybenzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic    acid;-   5-{2-[5-chloro-2-(chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-{2-[5-chloro-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-{2-[5-chloro-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-{2-[5-chloro-2-(3,4-dichlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)-phenyl]-1-enyl}-nicotinic    acid;-   5-{2-[5-chloro-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-{2-[5-chloro-2-(4-methoxybenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-{2-[5-bromo-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-2-[5-bromo-2-(4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-{2-[5-bromo-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5{2-[5-bromo-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-{2-[5-bromo-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-{2-[5-bromo-2-(4-methoxybenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-{2-[5-bromo-2-(cyclohexylmethoxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-{2-[5-trifluoromethyl-2-4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-{2-[5-trifluoromethyl-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   5-{2-[5-trifluoromethyl-2-(cyclohexylmethoxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid;-   6-{2-[5-chloro-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylic    acid;-   6-{2-[5-chloro-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylic    acid;-   6-{2-[5-chloro-2-(4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-pyridine    2-carboxylic acid;-   6-{2-[5-chloro-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-pyridine    2-carboxylic acid;-   3-{2-[5-methylsulfonyl-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic    acid;-   3-{2-[5-methylsulfonyl-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic    acid;-   3-{2-[5-methylsulfonyl-2-(4-fluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic    acid;-   3-{2-[5-methanesulfonyl-2-(4-fluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic    acid;-   3-{2-[5-methylsulfonyl-2-(2,4-difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic    acid;-   3-{2-[5-methanesulfonyl-2-(2,4-difluoro-benzyloxy)-phenyl]cyclopent-1-enyl}-benzoic    acid;-   3-{2-[2-(2,4-difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic    acid;-   3-{2-[2-(4-chloro-2-fluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic    acid;-   3-{2-[2-(4-methoxy-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic    acid;-   3-{2-[5-cyano-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic acid;-   3-{2-[5-cyano-2-(2,4-difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic    acid;-   2-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-pyrimidine-4-carboxylic    acid;-   6-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-pyridine-2-carboxylic    acid;-   6-{2-[5-methyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic    acid;-   6-{2-[5-methyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic    acid;-   2-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-4-carboxylic    acid;-   2-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-4-carboxylic    acid;-   4-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic    acid;-   4-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic    acid;-   6-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-aminopyrazine-2-carboxylic    acid;-   2-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4    carboxylic acid;-   2-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4-carboxylic    acid;-   6-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-pyrazine-2-carboxylic    acid;-   3-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoic    acid;-   6-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic    acid;-   6-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic    acid;-   6-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic    acid;-   3-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoic    acid;-   3-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoic    acid;-   3-{2-[5-trifluoromethyl-2-(2-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoic    acid;-   3-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-acetamidobenzoic    acid;-   3-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-acetamidobenzoic    acid;-   3-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-acetamidobenzoic    acid;-   3-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoic    acid;-   3-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoic    acid;-   3-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoic    acid;-   3-{2-[5-bromo-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoic    acid;-   3-{2-[5-bromo-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoic    acid;-   3-{2-[5-bromo-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoic    acid;-   5-{2-[trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}nicotinic    acid N-oxide;-   5-{2-[5-fluoro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(propionamido)benzoic    acid;-   5-{2-[5-methyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(propionamido)benzoic    acid;-   5-{2-[5-methyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(propionamido)benzoic    acid;-   5-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-2-methylbenzoic    acid;-   5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-propionylaminobenzoic    acid;-   2-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}isonicotinic    acid;-   2-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}isonicotinic    acid;-   2-{2-[5-chloro-2-benzyloxyphenyl]cyclopent-1-enyl}isonicotinic acid;-   2-{2-[5-bromo-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}isonicotinic    acid;-   5-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-3-propionylaminobenzoic    acid;-   5-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-3    isobutyrylaminobenzoic acid;-   5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl-}-3-(2-oxo-pyrrolidin-1-yl)benzoic    acid;-   5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-pyrrolidin-1-yl)benzoic    acid;-   5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-pyrrolidin-1-yl)benzoic    acid;-   5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-(2-oxo-piperidin-1-yl)benzoic    acid;-   5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-piperidin-1-yl)benzoic    acid;-   5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-piperidin-1-yl)benzoic    acid;-   6-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylic    acid;-   6-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylic    acid;-   6-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylic    acid;-   5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoic    acid;-   5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoic    acid;-   5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoic    acid;-   5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoic    acid;-   5-{2-[5-chloro-2-(2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoic    acid;-   5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoic    acid;-   5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoic    acid;-   5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-methanesulphonylaminobenzoic    acid;-   5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoic    acid;-   5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-acetamidobenzoic    acid;-   5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-acetamidobenzoic    acid;-   5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-acetamidobenzoic    acid;-   5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-acetamidobenzoic    acid;-   5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-acetamidobenzoic    acid;-   5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopenten-1-enyl}-3-acetamidobenzoic    acid;-   5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(morpholin-4-yl)benzoic    acid;-   5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(morpholin-4-yl)benzoic    acid;-   5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopenten-1-enyl}-3-(morpholin-4-yl)benzoic    acid;-   5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methylaminobenzoic    acid;-   5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methylaminobenzoic    acid;-   5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-methylaminobenzoic    acid;-   2-{2-[5-trifluoromethyl-2-(2,4-diflurobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-4-carboxylic    acid;-   2-{2-[5-bromo-2-(2,4-diflurobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-4-carboxylic    acid;-   2-{2-[5-bromo-2-(benzyloxy)phenyl]cyclopent-1-enyl}-pyridine-4-carboxylic    acid;-   2-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-5-amino-6-carboxylic    acid;-   2-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-aminopyrazine-6-carboxylic    acid;-   3-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoic    acid;-   3-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoic    acid;-   6-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylic    acid;-   5-2-[5-trifuoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1enyl}-3-(morpholin-4-yl)benzoic    acid;-   5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopenten-1-enyl)-3-morpholin-4-ylbenzoic    acid;-   5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopenten-1-enyl}-3-(morpholin-4-yl)benzoic    acid;-   5-{2-[5-chloro-2,4-difluorobenzyloxy)phenyl]cyclopenten-1-enyl}-3-methanesulphonylaminobenzoic    acid;-   5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-methanesulphonylamino    benzoic acid;-   5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-diethylaminobenzoic    acid;-   6-{2-[5-methyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylic    acid;-   6-{2-[5-methyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylic    acid;-   6-{2-[5-fluoro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-pyridine-2-carboxylic    acid;-   6-{2-[5-fluoro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-pyridine-2-carboxylic    acid;-   6-{2-[5-fluoro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic    acid;-   6-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridazine    carboxylic acid;-   6-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-pyridazine-carboxylic    acid;-   6-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridazine-4-carboxylic    acid;-   5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}2-methylbenzoic    acid;-   5-[2-(2-(4-fluorobenzyloxy)-5-chlorophenyl)cyclopent-1-enyl]-2-methylbenzoic    acid;-   5-[2-(2-(4-fluorobenzyloxy)-5-chlorophenyl)cyclopent-1-enyl]-2-fluorobenzoic    acid;-   5-[2-(2-benzyloxy)-5-chlorophenyl)cyclopent-1-enyl]-2-fluorobenzoic    acid;-   5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}nicotinic    acid;-   4-{2-[2-(benzyloxy)phenyl]cyclopent-1-enyl}-benzoic acid;-   4-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}benzoic acid;-   3-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoic    acid;-   3-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}5-methylbenzoic    acid;-   3-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoic    acid;-   3-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}5-methylbenzoic    acid;-   3-{2-[5-2-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoic    acid;-   3-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoic    acid;-   3-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoic    acid;-   3-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}5-fluorobenzoic    acid;-   3-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl-5-fluorobenzoic    acid;-   2-{2-[2-(4-fluorobenzyloxy)phenyl]-cyclopent-1-enyl}isonicotinic    acid;-   6-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic    acid;-   6-{2-[5-chloro-2-(4-bromobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic    acid;-   6-{2-[5-chloro-2-(2-chloro-4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic    acid;-   6-(2)-[5-chloro-2-(2,4,6-trifluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic    acid;-   6-{2-[5-chloro-2-(2,6-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-pyridine-2-carboxylic-acid;-   6-{2-[5-chloro-2-(2-fluoro-4-trifluoromethylbenzyloxy)phenyl]cyclopent-1-enyl}-pyridine-2-carboxylic    acid;-   6-{2-[5-chloro-2-(3,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic    acid;-   6-{2-[5-chloro-2-(2,3-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-pyridine-2-carboxylic    acid;-   6-{2-[5-chloro-2-(4-methylbenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic    acid;-   6-{2-[5-chloro-2-(4-trifluoromethylbenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic    acid;-   3-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-aminobenzoic    acid;-   2-{2-([5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4-carboxylic    acid;-   5-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-2-acetamidobenzoic    acid;-   3-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-fluorobenzoic    acid;-   5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-2-methylbenzoic    acid;-   5-{2-[5-chloro-2-(2,4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopyrrolidin-1-yl)benzoic    acid;-   5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopyrrolidin-1-yl)benzoic    acid;-   5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopyrrolidin-1-yl)benzoic    acid;-   5-{2-[5-chloro-2-(2,4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopiperidin-1-yl)benzoic    acid;-   5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopiperidin-1-yl)benzoic    acid; and-   5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopiperidin-1-yl)benzoic    acid    and pharmaceutically acceptable derivatives thereof.

Preferred compounds include the compounds of Examples 19, 29, 32, 52,90, 140 and 153.

Preferably compounds are selective for EP₁ over EP₃. More preferably thecompounds are 100 fold selective, more preferably 1000 fold selectivefor EP₁ over EP₃.

The invention is described using the following definitions unlessotherwise indicated.

The term “pharmaceutically acceptable derivative” means anypharmaceutically acceptable salt, ester, salt of such ester or solvateof the compounds of formula (I), or any other compound which uponadministration to the recipient is capable of providing (directly orindirectly) a compound of formula (I) or an active metabolite or residuethereof.

It will be appreciated by those skilled in the art that the compounds offormula (I) may be modified to provide pharmaceutically acceptablederivatives thereof at any of the functional groups in the compounds,and that the compounds of formula (I) may be derivatised at more thanone position.

It will be appreciated that, for pharmaceutical use, the salts referredto above will be physiologically acceptable salts, but other salts mayfind use, for example in the preparation of compounds of formula (I) andthe physiological acceptable salts thereof. Pharmaceutically acceptablesalts include those described by Berge, Bighley and Monkhouse, J. Pharm.Sci., 1977, 66, 1-19. The term “pharmaceutically acceptable salts”refers to salts prepared from pharmaceutically acceptable non-toxicbases including inorganic bases and organic bases. Salts derived frominorganic bases include aluminum, ammonium, calcium, copper, ferric,ferrous, lithium, magnesium, manganic salts, manganous, potassium,sodium, zinc, and the like. Particularly preferred are the ammonium,calcium, magnesium, potassium, and sodium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropyl amine,tromethamine, and the like. When the compound of the present inventionis basic, salts may be prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic adds. Such acidsinclude acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic add, and the like. Particularly preferred are citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaricacid.

Preferred examples of pharmaceutically acceptable salts include thoseformed from maleic, fumaric, benzoic, ascorbic, pamoic, succinic,bismethylenesalicylic, methanesulfonic, ethanedisulfonic, propionic,tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic,itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic,cyclohexylsulfamic, phosphoric and nitric acids.

The salts and/or solvates of the compounds of the formula (I) which arenot pharmaceutically acceptable may be useful as intermediates in thepreparation of pharmaceutically acceptable salts and/or solvates ofcompounds of formula (I) or the compounds of the formula (I) themselves,and as such form another aspect of the present invention.

The compounds of formula (I) may be prepared in crystalline ornon-crystalline form, and crystalline, may be optionally hydrated orsolvated. This invention includes in its scope stoichiometric hydratesas well as compounds containing variable amounts of water.

Suitable solvates include pharmaceutically acceptable solvates, such ashydrates.

Solvates include stoichiometric solvates and non-stoichiometricsolvates.

The terms “halogen” or “halo” are used to represent fluorine, chlorine,bromine or iodine.

The term “alkyl” as a group or part of a group means a straight,branched or cyclic chain alkyl group or combinations thereof, forexample a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl,pentyl, hexyl, 1,1-dimethylethyl, cyclopentyl or cyclohexyl orcombinations thereof such as cyclohexylmethyl and cyclopentylmethyl.Unless otherwise defined, preferably “alkyl” is C₁₋₈alkyl, morepreferably “alkyl” is C₁₋₆alkyl.

The term “alkoxy” as a group or as part of a group means a straight,branched or cyclic chain alkyl group having an oxygen atom attached tothe chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, s-butoxy, t-butoxy group, pentoxy, hexyloxy group,cyclopentoxy or cyclohexyloxy group. Preferably “alkoxy” is C₁₋₆ alkoxy.

The term “haloalkyl” means an alkyl group, including straight, branchedor cyclic structures, of the indicated number of carbon atoms in whichone or more hydrogen atoms have been replaced by halogen atoms, with upto complete substitution of all hydrogen atoms with halo groups.Preferably “haloalkyl” is C₁₋₆haloalkyl, C₁₋₆haloalkyl, for example,includes C₁₋₆fluoroalkyl, e.g. CF₃, CF₂CF₃ and the like.

The term “haloalkoxy” means an alkoxy group, including straight,branched or cyclic structures, of the indicated number of carbon atomsin which one or more hydrogen atoms have been replaced by halogen atoms,with up to complete substitution of all hydrogen atoms with halo groups.Preferably “haloalkoxy” is C₁₋₆haloalkoxy. C₁₋₆haloalkoxy, for example,includes C₁₋₆fluoroalkoxy e.g. OCF₃, OCF₂CF₃ and the like.

The term “alkenyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon double bond, wherein hydrogen may be replaced by anadditional carbon to carbon double bond. Preferably “alkenyl” isC₂₋₆alkenyl. C₂₋₆alkenyl, for example, includes ethenyl, propenyl,1-methylethenyl, butenyl and the like.

The term “heterocyclyl” as a group or as part of a group means anaromatic or non-aromatic five or six membered ring which contains from 1to 4 heteroatoms selected from nitrogen, oxygen or sulfur andunsubstituted or substituted by, for example, up to three substituents.Examples of 5-membered heterocyclyl groups include furyl, dioxalanyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,triazolyl, triazinyl, isothiazolyl, isoxazolyl, thiophenyl, pyrazolyl ortetrazolyl. Examples of 6-membered heterocyclyl groups are pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or tetrazinyl.

The term “aryl” as a group or part of a group means a 5- or 6 memberedaromatic ring, for example phenyl, or a 7 to 12 membered bicyclic ringsystem where at least one of the rings is aromatic, for examplenaphthyl. An aryl group may be optionally substituted by one or moresubstituents, for example up to 4, 3 or 2 substituents. Preferably thearomatic group is phenyl.

The term “heteroaryl” as a group or as part of a group means amonocyclic five or six membered aromatic ring, or a fused bicyclicaromatic ring system comprising two of such monocyclic five or sixmembered aromatic rings. These heteroaryl rings contain one or moreheteroatoms selected from nitrogen, oxygen or sulfur, where N-oxides,sulfur oxides and sulfur dioxides are permissible heteroatomsubstitutions. A heteroaryl group may be optionally substituted by oneor more substituents, for example up to 3 or up to 2 substituents.Examples of “heteroaryl” used herein include furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl,pyrimidinyl, quinolinyl, isoquinolinyl, benzofuryl, benzothienyl,indolyl, and indazolyl.

The term “bicyclic heterocyclyl” when used herein means a fused bicyclicaromatic or non-aromatic bicyclic heterocyclyl ring system comprising upto four, preferably one or two, heteroatoms each selected from oxygen,nitrogen and sulphur. Each ring may have from 4 to 7, preferably 5 or 6,ring atoms. A bicyclic heteroaromatic ring system may include acarbocyclic ring. Examples of bicyclic heterocyclyl groups includequinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pyridopyrazinyl,benzoxazolyl, benzothiophenyl, benzimidazolyl, benzothiazolyl,benzoxadiazolyl, benzthiadiazolyl, indolyl, benztriazolyl ornaphthyridinyl.

When the heteroatom nitrogen replaces a carbon atom in an alkyl group,or when nitrogen is present in a heteroaryl, heterocyclyl or bicyclicheterocyclyl group, the nitrogen atom will, where appropriate besubstituted by one or two substituents selected from hydrogen andC₁₋₈alkyl, preferably hydrogen and C₁₋₆-alkyl, more preferably hydrogen.

Optional substituents for alkyl or alkenyl groups are OH, CO₂R⁴, NR⁴R⁵,(O), OC₁₋₆alkyl or halo, wherein R⁴ and R⁵ are as herein before defined.An alkyl or alkenyl group may be substituted by one or more optionalsubstituents, for example up to 5, 4, 3, or 2 optional substituents.

Unless otherwise defined, optional substituents for aryl, heteroaryl orheterocyclyl moieties as a group or part of a group are selected fromoptionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆alkoxy andhalogen. Alternative optional substituants include C₁₋₆alkyl, C₁₋₆alkoxyand halogen.

Compounds of formula (I) can be prepared as set forth in the followingschemes and in the examples. The following processes form another aspectof the present invention.

For example, compounds of formula (I) may be prepared by the generalroute below:

wherein L¹, L², are leaving groups for example halo, or triflate; L³ andL⁴ is an activating group, for example selected from stannanes includingtrialkylstannane, and boranes including boronic acid and boronate; P isa protecting group, for example methyl, ethyl or substituted benzylesters; and A, R⁸, R⁹ and R^(x) are as defined for compounds of formula(I). L¹ can be converted to L¹′, wherein L¹′ is an activating group forexample a stannane or a boronic acid or boronic ester, and in thissituation L⁴ can be halo or triflate.

Alternatively compounds of formula (I) may be prepared according to theroute described below.

wherein L¹, L², L³, L⁴ and P are as defined above and A, R⁸, R⁹ andR^(x) are as defined for compounds of formula (I). L¹ can be convertedto L¹′, wherein L¹′ is an activating group, for example, a stannane or aboronic acid or boronic ester, and in this situation L⁴ can be halo ortriflate.

The preparation and reactions of boronic acids and esters is reviewed inSuzuki et al, Synth. Commun., 1981, 11, 513; Martin et al, Acta. Chim.Scand., 1993, 47, 221; and Miyaura et al, Chem. Rev., 1995, 95, 2457.

Certain substituents in reaction intermediates and compounds of formula(I) may be converted to other substituents by conventional methods knownto those skilled in the art.

For example, when R^(x) is methyl, cleavage of the ether to give thephenol is carried out using, for example, sodium methanethiolate.Conversion to another R^(x) group, for example a substituted benzylgroup, may be effected by reaction of the phenol with a suitablesubstituted benzyl bromide. The skilled person will appreciate thatconversion of the protecting group P to another protecting group P mayalso occur under the reaction conditions used. When R^(x) is benzyl,cleavage of the ether to give the phenol may be carried out using, forexample, HBr in acetic acid. The resulting phenol can then be convertedto another group R^(x) as described above.

It will be appreciated by those skilled in the art that it may benecessary to protect certain reactive substituents during some of theabove procedures. Standard protection and deprotection techniques, suchas those described in Greene T. W. ‘Protective groups in organicsynthesis’, New York, Wiley (1981), can be used. For example, carboxylicacid groups can be protected as esters. Deprotection of such groups isachieved using conventional procedures-known in the art. It will beappreciated that protecting groups may be interconverted by conventionalmeans.

Cyclopentene intermediates of the formula:

wherein L¹, L² are as defined above and R⁸ and R⁹ are as hereinbeforedefined for compounds of formula (I) are commercially available or maybe readily prepared according to known methods.Compounds of the formula:

wherein L⁴ is as hereinbefore defined, and R^(x) and R² are as definedfor compounds of formula (I) are commercially available, or may readilybe prepared by methods known to those skilled in the art, for examplefrom suitable commercially available anisoles or phenols using methodsas described in the examples.

Compounds of the formula:L³-A-R¹-Pwherein L³ and P are as defined above and R¹ and A are as hereinbeforedefined for compounds of formula (I) are commercially available or mayreadily be prepared, for example, from suitable halobenzoic acid estersaccording to known methods, for example using methods as described inthe examples.

It is to be understood that the present invention encompasses allisomers of formula (I) and their pharmaceutically acceptablederivatives, including all geometric, tautomeric and optical forms, andmixtures thereof (e.g. racemic mixtures). Where additional chiralcentres are present in compounds of formula (I), the present inventionincludes within its scope all possible diastereoismers, includingmixtures thereof. The different isomeric forms may be separated orresolved one from the other by conventional methods, or any given isomermay be obtained by conventional synthetic methods or by stereospecificor asymmetric syntheses.

The compounds of the invention bind to the EP₁ receptor and aretherefore useful in treating EP₁ receptor mediated diseases.

In view of their ability to bind to the EP₁ receptor, the compounds ofthe invention may be useful in the treatment of the disorders thatfollow. Thus, the compounds of formula (I) may be useful as analgesics.For example they may be useful in the treatment of chronic articularpain (e.g. rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis,gouty arthritis and juvenile arthritis) including the property ofdisease modification and joint structure preservation; musculoskeletalpain; lower back and neck pain; sprains and strains; neuropathic pain;sympathetically maintained pain; myositis; pain associated with cancerand fibromyalgia; pain associated with migraine; pain associated withinfluenza or other viral infections, such as the common cold; rheumaticfever; pain associated with functional bowel disorders such as non-ulcerdyspepsia, non-cardiac chest pain and irritable bowel syndrome; painassociated with myocardial ischemia; post operative pain; headache;toothache; and dysmenorrhea. The compounds of the invention may also beuseful in the treatment of visceral pain.

The compounds of the invention may be particularly useful in thetreatment of neuropathic pain. Neuropathic pain syndromes can developfollowing neuronal injury and the resulting pain may persist for monthsor years, even after the original injury has healed. Neuronal injury mayoccur in the peripheral nerves, dorsal roots, spinal cord or certainregions in the brain. Neuropathic pain syndromes are traditionallyclassified according to the disease or event that precipitated them.Neuropathic pain syndromes include: diabetic neuropathy; sciatica;non-specific lower back pain; multiple sclerosis pain; fibromyalgia;HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia;and pain resulting from physical trauma, amputation, cancer, toxins orchronic inflammatory conditions. These conditions are difficult to treatand although several drugs are known to have limited efficacy, completepain control is rarely achieved. The symptoms of neuropathic pain areincredibly heterogeneous and are often described as spontaneous shootingand lancinating pain, or ongoing, burning pain. In addition, there ispain associated with normally non-painful sensations such as “pins andneedles” (paraesthesias and dysesthesias), increased sensitivity totouch (hyperesthesia), painful sensation following innocuous stimulation(dynamic, static or thermal allodynia), increased sensitivity to noxiousstimuli (thermal, cold, mechanical hyperalgesia), continuing painsensation after removal of the stimulation (hyperpathia) or an absenceof or deficit in selective sensory pathways (hypoalgesia).

The compounds of formula (I) may also be useful in the treatment offever.

The compounds of formula (I) may also be useful in the treatment ofinflammation, for example in the treatment of skin conditions (e.g.sunburn, bums, eczema, dermatitis, psoriasis); ophthalmic diseases suchas glaucoma, retinitis, retinopathies, uveitis and of acute injury tothe eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma,bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome,pigeon fancier's disease, farmer's lung, chronic obstructive pulmonarydisease, (COPD); gastrointestinal tract disorders (e.g. aphthous ulcer,Crohn's disease, atopic gastritis, gastritis varialoforme, ulcerativecolitis, coeliac disease, regional ileitis, irritable bowel syndrome,inflammatory bowel disease, gastrointestinal reflux disease); organtransplantation; other conditions with an inflammatory component such asvascular disease, migraine, periarteritis nodosa, thyroiditis, aplasticanaemia, Hodgkin's disease, sclerodoma, myaesthenia gravis, multiplesclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome,polymyositis, gingivitis, myocardial ischemia, pyrexia, systemic lupuserythematosus, tendinitis, bursitis, and Sjogren's syndrome.

The compounds of formula (I) are also useful in the treatment ofimmunological diseases such as autoimmune diseases, immunologicaldeficiency diseases or organ transplantation. The compounds of formula(I) are also effective in increasing the latency of HIV infection.

The compounds of formula (I) are also useful in the treatment ofdiseases of abnormal platelet function (e.g. occlusive vasculardiseases).

The compounds of formula (I) are also useful for the preparation of adrug with diuretic action.

The compounds of formula (I) are also useful in the treatment ofimpotence or erectile dysfunction.

The compounds of formula (I) are also useful in the treatment of bonedisease characterised by abnormal bone metabolism or resorbtion such asosteoporosis (especially postmenopausal osteoporosis), hyper-calcemia,hyperparathyroidism, Paget's bone diseases, osteolysis, hypercalcemia ofmalignancy with or without bone metastases, rheumatoid arthritis,periodontitis, osteoarthritis, ostealgia, osteopenia, cancer cacchexia,calculosis, lithiasis (especially urolithiasis), solid carcinoma, goutand ankylosing spondylitis, tendinitis and bursitis.

The compounds of formula (I) are also useful for attenuating thehemodynamic side effects of non-steroidal anti-inflammatory drugs(NSAID's) and cyclooxygenase-2 (COX-2) inhibitors.

The compounds of formula (I) are also useful in the treatment ofcardiovascular diseases such as hypertension or myocardiac ischemia;functional or organic venous insufficiency; varicose therapy;haemorrhoids; and shock states associated with a marked drop in arterialpressure (e.g. septic shock).

The compounds of formula (I) are also useful in the treatment ofneurodegenerative diseases and neurodegeneration such as dementia,particularly degenerative dementia (including senile dementia,Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson'sdisease and Creutzfeldt-Jakob disease, ALS, motor neuron disease);vascular dementia (including multi-infarct dementia); as well asdementia associated with intracranial space occupying lesions; trauma;infections and related conditions (including HIV infection); metabolism;toxins; anoxia and vitamin deficiency; and mild cognitive impairmentassociated with ageing, particularly Age Associated Memory Impairment.The compounds of formula (I) are also useful in the treatment ofneuroprotection and in the treatment of neurodegeneration followingstroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinalcord injury or the like.

The compounds of formula (I) are also useful in the treatment oftinnitus.

The compounds of formula (I) are also useful in preventing or reducingdependence on, or preventing or reducing tolerance or reverse toleranceto, a dependence-inducing agent. Examples of dependence inducing agentsinclude opioids (e.g. morphine), CNS depressants (e.g. ethanol),psychostimulants (e.g. cocaine) and nicotine.

The compounds of formula (I) are also useful in the treatment ofcomplications of Type 1 diabetes (e.g. diabetic microangiopathy,diabetic retinopathy, diabetic nephropathy, macular degeneration,glaucoma), nephrotic syndrome, aplastic anaemia, uveitis, Kawasakidisease and sarcoidosis.

The compounds of formula (I) are also useful in the treatment of kidneydysfunction (nephritis, particularly mesangial proliferativeglomerulonephritis, nephritic syndrome), liver dysfunction (hepatitis,cirrhosis), gastrointestinal dysfunction (diarrhoea) and colon cancer.

It is to be understood that reference to treatment includes bothtreatment of established symptoms and prophylactic treatment, unlessexplicitly stated otherwise.

According to a further aspect of the invention, we provide a compound offormula (I) or a pharmaceutically acceptable derivative thereof for usein human or veterinary medicine.

According to another aspect of the invention, we provide a compound offormula (I) or a pharmaceutically acceptable derivative thereof for usein the treatment of a condition which is mediated by the action of PGE₂at EP₁ receptors.

According to a further aspect of the invention, we provide a method oftreating a human or animal subject suffering from a condition which ismediated by the action of PGE₂ at EP₁ receptors which comprisesadministering to said subject an effective amount of a compound offormula (I) or a pharmaceutically acceptable derivative thereof.

According to a further aspect of the invention we provide a method oftreating a human or animal subject suffering from a pain, inflammatory,immunological, bone, neurodegenerative or renal disorder, which methodcomprises administering to said subject an effective amount of acompound of formula (I) or a pharmaceutically acceptable derivativethereof.

According to a yet further aspect of the invention we provide a methodof treating a human or animal subject suffering from inflammatory pain,neuropathic pain or visceral pain which method comprises administeringto said subject an effective amount of a compound of formula (I) or apharmaceutically acceptable derivative thereof.

According to another aspect of the invention, we provide the use of acompound of formula (I) or a pharmaceutically acceptable derivativethereof for the manufacture of a medicament for the treatment of acondition which is mediated by the action of PGE₂ at EP₁ receptors.

According to another aspect of the invention we provide the use of acompound of formula (I) or a pharmaceutically acceptable derivativethereof for the manufacture of a medicament for the treatment orprevention of a condition such as a pain, inflammatory, immunological,bone, neurodegenerative or renal disorder.

According to another aspect of the invention we provide the use of acompound of formula (I) or a pharmaceutically acceptable derivativethereof for the manufacture of a medicament for the treatment orprevention of a condition such as inflammatory pain, neuropathic pain orvisceral pain.

The compounds of formula (I) and their pharmaceutically acceptablederivatives are conveniently administered in the form of pharmaceuticalcompositions. Such compositions may conveniently be presented for use inconventional manner in admixture with one or more physiologicallyacceptable carriers or excipients.

Thus, in another aspect of the invention, we provide a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof adapted for use in human or veterinarymedicine.

The compounds of formula (I) and their pharmaceutically acceptablederivatives may be formulated for administration in any suitable manner.They may, for example, be formulated for topical administration oradministration by inhalation or, more preferably, for oral, transdermalor parenteral administration. The pharmaceutical composition may be in aform such that it can effect controlled release of the compounds offormula (I) and their pharmaceutically acceptable derivatives.

For oral administration, the pharmaceutical composition may take theform of, for example, tablets (including sub-lingual tablets), capsules,powders, solutions, syrups or suspensions prepared by conventional meanswith acceptable excipients.

For transdermal administration, the pharmaceutical composition may begiven in the form of a transdermal patch, such as a transdermaliontophoretic patch.

For parenteral administration, the pharmaceutical composition may begiven as an injection or a continuous infusion (e.g. intravenously,intravascularly or subcutaneously). The compositions may take such formsas suspensions, solutions or emulsions in oily or aqueous vehicles andmay contain formulatory agents such as suspending, stabilising and/ordispersing agents. For administration by injection these may take theform of a unit dose presentation or as a multidose presentationpreferably with an added preservative. Alternatively for parenteraladministration the active ingredient may be in powder form forreconstitution with a suitable vehicle.

The compounds of the invention may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

The EP₁ receptor compounds for use in the instant invention may be usedin combination with other therapeutic agents, for example COX-2inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib,parecoxib or COX-189; 5-lipoxygenase inhibitors; NSAID's, such asdiclofenac, indomethacin, nabumetone or ibuprofen; leukotriene receptorantagonists; DMARD's such as methotrexate; adenosine A1 receptoragonists; sodium channel blockers, such as lamotrigine; NMDA receptormodulators, such as glycine receptor antagonists; gabapentin and relatedcompounds; tricyclic antidepressants such as amitriptyline; neuronestabilising antiepileptic drugs; mono-aminergic uptake inhibitors suchas venlafaxine; opioid analgesics; local anaesthetics; 5HT₁ agonists,such as triptans, for example sumatriptan, naratriptan, zolmitriptan,eletriptan, frovatriptan, almotriptan or rizatriptan; nicotinic acetylcholine (nACh) receptor modulators; glutamate receptor modulators, forexample modulators of the NR2B ssubtype; EP₄ receptor ligands; EP₂receptor ligands; EP₃ receptor ligands; EP₄ antagonists; EP₂ antagonistsand EP₃ antagonists; cannabanoid receptor ligands; bradykinin receptorligands and vanilloid receptor ligand. When the compounds are used incombination with other therapeutic agents, the compounds may beadministered either sequentially or simultaneously by any convenientroute.

Additional COX-2 inhibitors are disclosed in U.S. Pat. No. 5,474,995U.S. Pat. No. 5,633,272; U.S. Pat. No. 5,466,823, U.S. Pat. No.6,310,099 and U.S. Pat. No. 6,291,523; and in WO 96/25405, WO 97/38986,WO 98/03484, WO 97/14691, WO99/12930, WO00/26216, WO00/52008,WO00/38311, WO01/58881 and WO02/1874.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablederivative thereof together with a further therapeutic agent or agents.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the invention. The individual components of such combinationsmay be administered either sequentially or simultaneously in separate orcombined pharmaceutical formulations.

When a compound of formula (I) or a pharmaceutically acceptablederivative thereof is used in combination with a second therapeuticagent active against the same disease state the dose of each compoundmay differ from that when the compound is used alone. Appropriate doseswill be readily appreciated by those skilled in the art.

A proposed daily dosage of compounds of formula (I) or theirpharmaceutically acceptable derivatives for the treatment of man is from0.01 to 30 mg/kg body weight per day and more particularly 0.1 to 10mg/kg body weight per day, calculated as the free base, which may beadministered as a single or divided dose, for example one to four timesper day The dose range for adult human beings is generally from 8 to2000 mg/day, such as from 20 to 1000 mg/day, preferably 35 to 200mg/day, calculated as the free base.

The precise amount of the compounds of formula (I) administered to ahost, particularly a human patient, will be the responsibility of theattendant physician. However, the dose employed will depend on a numberof factors including the age and sex of the patient, the precisecondition being treated and its severity, and the route ofadministration.

No unacceptable toxicological effects are expected with compounds of theinvention when administered in accordance with the invention.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following non-limiting Examples illustrate the preparation ofpharmacologically active compounds of the invention.

EXAMPLES

Mass Directed Auto-Purification Systems

Hardware

-   Waters 600 gradient pump-   Waters 2700 sample manager-   Waters Reagent Manager-   Micromass ZMD mass spectrometer-   Gilson 202—fraction collector-   Gilson Aspec—waste collector    Software-   Micromass Masslynx version 3.5    Column

The column used is typically a Supelco ABZ+ column whose dimensions are10 mm internal diameter by 100 mm in length. The stationary phaseparticle size is 5 μm.

Solvents

-   A. Aqueous solvent=Water+0.1% Formic Acid-   B. Organic solvent=MeCN: Water 95:5+0.05% Formic Acid-   Make up solvent=MeOH: Water 80:20+50 mMol Ammonium Acetate-   Needle rinse solvent=MeOH:Water:DMSO (N,N-dimethyl sulfoxide)    80:10:10    Methods

There are five methods used depending on the analytical retention timeof the compound of interest.

They all have a 15-minute runtime, which comprises of a 10-minutegradient followed by a 5-minute column flush and re-equilibration step.

-   MDP 1.5-2.2=0-30% B-   MDP 2.0-2.8=5-30% B-   MDP 2.5-3.0=15-55% B-   MDP 2.84.0=30-80% B-   MDP 3.8-5.5=50-90% B    Flow Rate

All of the above methods have a flow rate of 20 ml/min.

Compound I: 4-Chloro-2-iodophenol

(Tetrahedron, 1995, 51, 8555)

2-Amino-4-chlorophenol (ex Aldrich) (50 g 0.35 mol) was dissolved in 2.5M hydrochloric acid (500 ml), cooled to 0° C. and a solution of sodiumnitrite (25.39, 0.37 mol) in water (50 ml) was slowly added over 20minutes at 0-5° C., stirred for 30 minutes, then a solution of potassiumiodide (70 g, 0.42 mol.) in water (100 ml) was added slowly at 0° C. Thereaction mixture was then allowed to warm to 10° C. over 3 hours. Theproduct was then extracted with ethyl acetate (200 ml), washed with 10%sodium bisulphite, water, and was dried over magnesium sulphate andevaporated down to dryness. The product was purified by columnchromatography with 5% ethylacetate in hexane to give an orange solid.wt.62 g. 70% yield.

Compound II: 2-Benzyloxy-5-chloro-iodobenzene

4-Chloro-2-iodophenol (57 g. 0.22M was dissolved in acetonitrile (500mls), caesium carbonate (72.6 g, 0.22M.) was added slowly giving rise toan exotherm (19-24° C.) over 30 minutes. The reaction mixture was thenkept at 24° C. for a further 5 hours. The reaction mixture was thenstirred at 40° C. for 4 hours, then stirred at room temperature overnight. The reaction mixture was filtered and evaporated down to apink/brown solid. After trituration with water (200 ml) the suspensionwas filtered and recrystallised from hexane (200 ml) giving the titlecompound 50.2 g, 65% yield. A second crop gave a further 22.7 g.

Total yield after drying 88%.

Rt=13.20 min.

Compound III: (2-Benzyloxy-5-chlorophenyl)-boronic Acid

(WO 01/19814 A2)

2-Benzyloxy-5-chlorophenyl iodide (5 g 0.0145 mol) in diethylether/tetrahydrofuran (100:30) was cooled to −100° C. n-Butyl lithium,1.6M solution in hexanes (10 mL, 0.016 mol) was added dropwise over 15min under nitrogen. The reaction mixture was then allowed to rise to−70° C. for 1 h. Triethylborate (9 mL, 0.03 mol) was added dropwiseunder nitrogen. The cooling bath was then removed and the reactionmixture was stirred at room temperature overnight. The reaction mixturewas then quenched with 2N hydrochloric acid (40 mL) and stirredvigorously at room temperature for 1 h. The product was then extractedwith ethyl acetate, dried over magnesium sulphate and evaporated down toan oil. Purification was carried out on a Biotage (90 g cartridge) withether/iso-hexane (50:50) to give the required product (wt; 2.8 g i.e.74% yield).

Compound IV: (2-Bromo-cyclopenten-1-enyl)-trimethylstannane

n-Butyllithium, 1.6M in hexanes, (58 mL, 92.0 mmol) in THF (50 mL) wascooled under nitrogen to −75° C. 1,2-Dibromocyclopentene (10.00 g, 44.3mmol) in dry THF (10 mL) was added dropwise over ˜10 minutes. Themixture was stirred at −75° C. for a further 20 minutes and then allowedto reach 0° C. The reaction mixture was then re-cooled to −75° C. andtrimethyltin chloride (8.85 g, 44.3 mmol) in THF (30 mL) was added,under nitrogen, over ˜10 minutes. After stirring at −75° C. for 30minutes the reaction was allowed to reach room temperature and thenstirred for 2 hours. The reaction mixture was then evaporated down to anoil and partitioned between brine and dichloromethane (100/200 mL).After shaking thoroughly, the organic layer was dried (magnesiumsulphate), filtered and evaporated to give an oil. (13.15 g, ˜80% pure).

¹H NMR (400 MHz CDCl₃) 0.25 (9H, s), 1.91-2.2 (2H, m), 2.38-2.47 (2H,m), 2.64-2.73 (2H, m).

Compound V: 6-Bromopyridine-2-carboxylic Acid Methyl Ester

6-Bromopyridine-2-carboxylic acid (6.000 g) was heated in refluxingmethanol (180 mL) containing conc. sulphuric acid (2 mL) for 4 hrs. Thereaction mixture was then cooled to ˜0° C. and conc. ammonia (4.8 mL)was added. The resulting solution was evaporated to give a whiteresidue. This white solid was partitioned between brine anddichloromethane (100/100 mL). After thorough shaking the organic layerwas dried (magnesium sulphate) and evaporated to give a white solid.(6.300 g, 98%).

¹H NMR (400 MHz, CDCl₃) 4.00 (3H, s), 7.66-7.74 (2H, m), 8.07-8.13 (1H,m).

Example 1 {2-[5-chloro-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid a) 3(2-Bromocyclopent-1-enyl)-benzoic Acid Ethyl Ester

1,2-Dibromocyclopentene (Ex Aldrich, 27,732-0) (5 g, 0.0221 mol),(3-ethoxycarbonylphenyl) boronic acid (Ex Combiblocks inc. BB-2117-005)(4.26 g, 0.0221 mol), Pd(0)[PPh₃]₄ (0.5 g) and potassium carbonate (5 g)were stirred at 80° C. under nitrogen for 18 h in dimethoxyethane (30mL). The reaction mixture was then filtered through Kieselguhr andevaporated down to an oil. Purification was carried out on a Biotage (90g column) using isohexane containing a gradient of dichloromethane(0-30%) to give the required product (wt: 1.15 g i.e. 30% yield)

¹H NMR (400 MHz, CDCl₃) 1.40 (3H, t, J=7 Hz), 2.00-2.12 (2H, m),2.75-2.94 (4H, m's), 4.39 (2H, q, J=7 Hz), 7.43 (1H, t, J=8 Hz), 7.85(1H, d, J=8 Hz), 7.96 (1H, d, J=8 Hz), 8.22 (1H, s).

LC/MS rt 3.82, [MH+9 295, 297.

b) 3-{2-[5-chloro-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic AcidEthyl Ester

3-(2-Bromocyclopent-1-enyl)-benzoic acid ethyl ester (0.148 g, 0.0005mol), Pd(0)[PPh₃]₄ (30 mg), potassium carbonate (0.2 g) and(2-benzyloxy-5-chlorophenyl) boronic acid (150 mg, 0.0005 mol) indimethoxyethane (5 mL) were refluxed for 17 h under nitrogen. Thereaction mixture was then filtered through Kieselghur and evaporateddown to an oil. Purification was carried out on a Water's separationpack (10 g) with dichloromethane/iso hexane giving the product (85 mg).

¹H NMR (400 MHz, CDCl₃) 1.31 (3H, t, J=7 Hz), 2.01-2.12 (2H, m),2.81-2.88 (4H, m's), 4.28 (2H, q, J=8 Hz), 4.93 (2H, s), 6.81 (1H, d,J=8 Hz), 7.02, (1H, d, J=2 Hz), 7.10-7.33 (8H, m's excess), 7.76-7.86(2H, m).

LC/MS rt 4.21, [MH+] 433.

c) 342-[5-chloro-2-(benzyloxy)-phenyl]-cyclopent-1-enyl-benzoic Acid

3-{2-[5-chloro-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic acidethyl ester (80 mg) was refluxed for 1 h in methanol/2N sodium hydroxide(10:10 mL). The reaction mixture was then evaporated down to 3 mL. 2NHydrochloric acid (10 mL) was added and the product extracted withdichloromethane (2×10 mL), dried over magnesium sulphate and evaporateddown to an oil which solidified on standing (wt: 70 mg).

¹H NMR (400 MHz, CDCl₃) 2.00-2.18 (2H, m), 2.80-3.50 (4H, m's), 4.94(2H, s), 6.82 (1H, d J=9 Hz), 7.02 (1H, d, J=2 Hz), 7.10-7.40 (8H, m'sexcess), 7.86 (1H, d, J=7 Hz), 7.90 (1H, s).

LC/MS RT=3.63 min [MH−] 403, 404.

Example 2 3-{2-[2-benzyloxy)-phenyl]-cyclopent-1-enyl]-benzoic acid a)3-{2-[2-(benzyloxy)-phenyl]-cyclopent-1-enyl-benzoic Acid

3-(2-Bromo-cyclopent-1-enyl] benzoic acid ethyl ester (0.148 g, 0.0005mol), tetrakis-triphenylphosphine palladium (o) (30 mg), potassiumcarbonate (0.200 g) and (2-benzyloxyphenyl) boronic Acid (0.110 g, 0.5mmol) in dimethoxyethane (5 mL) were refluxed for 17 h under nitrogen.The reaction mixture was then filtered through Keiselghur and evaporateddown to an oil. Purification was carried out on a Waters separation pack(10 g) cartridge with dichloromethane/iso hexane giving the product (120mg).

¹H NMR (400 MHz, CDCl₃) 1.30 (3H, t, J=7 Hz), 2.01-2.13 (2H, m),2.84-2.99 (4H, m's), 4.27 (2H, q, J=7 Hz), 5.00 (2H, s), 6.85 (1H, td,J=1 Hz, J=7 Hz), 6.92 (1H, d, J=8 Hz), 7.02 (1H, d, J=7 Hz), 7.11-7.34(8H, m's excess), 7.76 (1H, d, J=8 Hz), 7.85 (1H, s).

LC/MS RT=4.09 min.

b) 3-{2-[2-(benzyloxy)-phenyl]cyclopent-1-enyl]-benzoic Acid

3-[2-(2-Benzyloxyphenyl)-cyclopent-1-enyl]benzoic acid ethyl ester (120mg) was refluxed for 1 h in methanol/2N sodium hydroxide (10/10 mL). Thereaction mixture was then evaporated down to 3 mL on a rotaryevaporator. 2N Hydrochloric acid was added. T he product was extractedwith dichloromethane (2×10 mL), dried over magnesium sulphate andevaporated down to an oil which solidified on standing (wt: 100 mg).

¹H NMR (400 MHz, CDCl₃) 2.01-2.13 (2H, m), 2.85-3.00 (4H, m's), 5.00(2H, s), 6.86 (1H, t, J=7 Hz), 6.92 (1H, d, J=8 Hz), 7.02 (1H, dd, J=2Hz, J=7 Hz), 7.12-7.35 (8H, m's excess), 7.82 (1H, d, J=8 Hz), 7.91 (1H,s).

LC/MS RT=3.81 min [MH+] 371, [MH−] 369.General Procedure 1

3-{2-Bromocyclopent-1-enyl)-benzoic Acid Ethyl Ester

1,2-Dibromocyclopentene (Aldrich) (5.000 g, 22.1 mmol),(3-ethoxycarbonylphenyl) boronic acid (Combiblocks) (4.260 g, 22.1mmol), tetrakistriphenylphosphinepalladium(0) (0.500 g) and potassiumcarbonate (5.000 g) were stirred at 80° C. under nitrogen for 18 h indimethoxyethane (30 mL). The reaction mixture was then filtered throughKieselguhr and evaporated down to give an oil.

Purification by chromatography using iso-hexane containing a gradient ofdichloromethane (0-30%) gave the required product (1.150 g, 30% yield).

General Procedure 2

3-(2-Bromo-cyclopent-1-enyl)benzoic Acid Ethyl Ester

(2-Bromo-cyclopent-1-enyl)trimethyl stannane (˜80% pure) (13.150 g, 43.7mmol), ethyl-3-iodobenzoate (24.000 g, 87.4 mmol), triphenylarsine(4.000 g) and tris(dibenzylideneacetone)palladium (0) (1.500 g), wereheated in dimethylformamide (20 mL) at 100° C., under nitrogen for 92hours. The reaction mixture was then filtered through highflo,thoroughly washed with dichloromethane, reduced to an oil, and purifiedby chromatography with iso-hexane containing ether (2%-50%) to give thetitle compound (4.000 g, 28%).

¹H NMR (400 MHz, CDCl₃), 1.40 (3H, t, J=7 Hz), 2.00-2.21 (2H, m),2.76-2.83 (2H, m), 2.80-2.91 (2H, m), 4.33-4.45 (2H, m), 7.43 (1H, t,J=8 Hz), 7.83 (1H, d, J=8 Hz), 7.92-7.98 (1H, d, J=8 Hz), 8.20 (1H, s).

LC/MS [MH+] 297 Rt=3.87 min.

5-(2-Bromocyclopent-1-enyl)nicotinic Acid Ethyl Ester

Prepared according to general procedure 2

-   (2-Bromocyclopent-1-enyl)trimethyl stannane (13.79, 44.30 mmol)-   ethyl-5-bromonicotinate (14.0 g, 60.0 mmol)-   tris(dibenzylideneacetone)palladium (0) (1.500 g)-   triphenylarsine (4.0 g)-   dimethylformamide (20 mL)-   Heated at 100° C. for 92 hours

Product (7.0 g, 56%).

LC/MS (CF104055-1) [MH+] 298

¹H NMR (400 MHz, CDCl₃), 1.42 (3H, t, J=7 Hz), 2.06-2.16 (2H, m),2.77-2.85 (2H, m), 2.86-2.93 (2H, m), 8.50 (1H, s), 9.00 (1H, d, J=2.2Hz), 9.15 (1H, d, J=2 Hz).

6-(2-Bromocyclopent-1-enyl)pyridine-2-carboxilic Acid Methyl Ester

Prepared using general procedure 2:

-   (2-Bromocyclopent-1-enyl)trimethylstannane (6.0 g, 19.4 mmol)-   6-bromopyridine-2-carboxylic acid methyl ester (6.0 g, 26.0 mmol-   tris(dibenzylideneacetone)palladium (0) (1.0 g)-   triphenylarsine (2.0 g) were heated at 115° C. for 40 hrs in    dimethylformamide (20 mL).

Product (2.7 g). This oil was carried through the next stage withoutfurther purification.

LC/MS (CF105919-1) [MH+] 284 Rt=3.21 min.General Procedure 3

3-{2-[5-chloro-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic AcidEthyl Ester

3-(2-Bromocyclopent-1-enyl)-benzoic acid ethyl ester (148 mg, 0.5 mmol),tetrakis(triphenylphosphine)palladium (0) (30 mg), potassium carbonate(0.20 g) and (2-benzyloxy-5-chlorophenyl) boronic acid (150 mg, 0.5mmol) in dimethoxyethane (5 mL) were refluxed for 17 h under nitrogen.The reaction mixture was then filtered through Kieselguhr and evaporateddown to an oil. Purification was carried out on a Water's separationpack (10 g) with dichloromethane/iso-hexane to give the product (85 mg).

LC/MS [MH+] 433 Rt=4.21 min.

¹NMR (400 MHz, CDCl₃) 1.31 (3H, t, J=7 Hz), 2.01-2.12 (2H, m), 2.81-2.88(4H, m), 4.28 (2H, q, J=7 Hz), 4.93 (2H, s), 6.81 (1H, d, J=9 Hz), 7.02(1H, J=2 Hz), 7.10-7.33 (8H, m), 7.76-7.86 (2H, m).

3-{2-[2-(benzyloxy)-phenyl]-cyclopent-1-enyl]-benzoic Acid Ethyl Ester

Prepared using general procedure 3

-   3-(2-Bromo-cyclopent-1-enyl]Benzoic add ethyl ester (148 mg, 0.5    mmol)-   tetrakis(triphenylphosphine)palladium (0) (30 mg)-   potassium carbonate (200 mg)-   (2-benzyloxyphenyl) boronic acid (110 mg, 0.5 mmol)-   dimethoxyethane (5 mL) were refluxed for 17 h under nitrogen.

Product (120 mg).

LC/MS: Rt=4.09 min.

¹NMR (400 MHz, CDCl₃) 1.30 (3H, t, J=7 Hz), 2.01-2.13 (2H, m), 2.84-2.99(4H, m), 4.28 (2H, q, J-7 Hz), 5.00 (2H, s), 6.85 (1H, td, J=7 Hz, J=7Hz), 6.92 (1H, d, J=8 Hz), 7.02 (1H, dd, J=2 Hz, J-7 Hz), 7.11-7.34 (8H,m), 7.76 (1H, d, J=8 Hz), 7.85 (1H, s).

3-{2-[5-Bromo-2-(methoxy)phenyl]-cyclopent-1-enyl}-benzoic Acid EthylEster

Prepared using general procedure 3

-   3-(2-Bromocyclopent-1-enyl)benzoic acid ethyl ester (1.00 g, 3.40    mmol)-   3-bromo-6-methoxyphenylboronic acid (1.656 g, 7.20 mmol)-   tetrakis(triphenylphosphine)palladium (0) (2.7 g) (200 mg)-   potassium carbonate (2.0 g)-   dimethoxyethane (10 mL)-   reflux 24 hours.-   product (416 mg, 35%).

¹H MNR (400 MHz, CDCl₃) 1.34 (3H, t, J=7 Hz), 2.03-2.13 (2H, m),2.79-2.85 (2H, m), 2.92-2.98 (2H, m), 3.61 (3H, s), 4.31 (2H, q, J=6.5Hz), 6.73 (1H, d, J=9 Hz), 7.13 (1H, d, J=2.5 Hz), 7.16-7.25 (2H, m),7.31 (1H, dd, J=2.5 Hz, J=11 Hz), 7.77-7.82 (1H, m), 7.85 (1H, s).

5-{2-[5-Chloro-2-(methoxy)phenyl]-cyclopent-1-enyl}-nicotinic Acid EthylEster

Prepared by general procedure 3

-   5-(2-Bromocyclopent-1-enyl)nicotinic acid ethyl ester (1.480 g, 5.0    mmol)-   3-chloro-6-methoxyphenylboronic acid (1.490 g, 8.0 mmol)-   tetrakis(triphenylphosphine)palladium (0) (0.300 g)-   potassium carbonate (2.000 g)-   dimethoxyethane (20 mL)-   reflux 92 hrs-   product (1.500 g, 85%).

LC/MS [MH+] 358 Rt=3.73 min.

¹H NMR (400 MHz, CDCl₃) 1.36 (3H, t, J=7 Hz), 2.07-2.26 (2H, m),2.82-2.88 (2H, m), 2.93-2.99 (2H, m), 3.63 (3H, s), 4.35 (2H, q, J=7Hz), 6.79 (1H, d, J=9 Hz), 6.98 (1H, d, J=3 Hz), 7.19 (1H, dd, J=3 Hz,J=11 Hz), 8.30 (1H, t, J=4 Hz), 8.45 (1H, d, J=2 Hz), 8.94 (1H, d, J=2Hz).

5-{2-[5-Bromo-2-(methoxy)-phenyl]-cyclopent-1-enyl}-nicotinic Acid EthylEster

Prepared by general procedure 3

-   5-(2-Bromocyclopent-1-enyl)-nicotinic acid ethyl ester (2.000 g, 6.7    mmol)-   3-bromo-6-methoxyphenylboronic acid (2.300 g, 10.0 mmol)-   tetrakis(triphenylphosphine)palladium (0) (0.300 g)-   anhydrous potassium carbonate (2.500 g)-   dimethoxyethane (20 mL)-   reflux 24 hrs-   product (1.100 g, 41%).

¹H MNR (400 MHz, CDCl₃) 1.36 (3H, t, J=7 Hz), 2.06-2.16 (2H, m),2.80-2.90 (2H, m) 2.91-2.99 (2H, m), 3.63 (3H, s), 4.35 (2H, q, J=7 Hz),6.74 (1H, d, J=4 Hz), 7.13 (1H, d, J=3 Hz), 7.33 (1H, dd, J=2 Hz, J=9.5Hz), 8.03 (1H, t, J=2 Hz), 8.45 (1H, d, J=2 Hz), 8.94 (1H, d, J=2Hz).

LC/MS (CF105233-1) [MH+] 404 Rt=3.77 min.

5-{2-[5-Trifluoromethyl-2-(methoxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared by general procedure 3

-   5-(2-Bromocyclopent-1-enyl}-nicotinic acid ethyl ester (1.480 g, 5.0    mmol)-   2-methoxy-5-trifluoromethylphenylboronic acid (1.750 g, 8.0 mmol)-   tetrakis(triphenylphosphine)palladium (0) (0.3000 g)-   potassium carbonate (2.0 g)-   dimethoxyethane (20 mL)-   reflux 24 hr-   product (2.00 g, 100%).

¹H NMR (400 MHz, CDCl₃) 1.34 (3H, t, J=7 Hz), 1.90-2.18 (2H, m),2.85-2.93 (2H, m), 2.94-2.32 (2H, m), 3.69 (3H, s), 4.33 (2H, q, J=7Hz), 6.93 (1H, d, J=8. Hz), 7.27 (1H, d, J=4 Hz), 7.50 (1H, dd, J=2 Hz,J=9 Hz), 8.00 (1H, t, J=8 Hz), 8.43 (1H, d, J=3 Hz), 8.94 (1H, d, J=3Hz).

LC/MS (CF104952-1) [MH+] 392 Rt=3.76 min.

6-{2-[5-Chloro-2-(methoxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylicAcid Methyl Ester

Prepared by general procedure 3

-   6-(2-Bromocyclopent-1-enyl}-pyridine-2-carboxylic acid methyl ester    (2.700 g, ˜60%, 9.5 mmol)-   3-chloro-6-methoxyphenylboronic acid (1.800 g, 10.0 mmol)-   tetrakis(triphenylphosphine)palladium (0) (0.500 g)-   potassium carbonate (2.500 g)-   dimethoxyethane (20 mL)-   reflux 24 hrs-   product (0.700 g, ˜74% pure).

LC/MS [MH+] 344 Rt=3.62.General Procedure 4

3-{2-[5-Bromo-2-(hydroxy)-phenyl]-cyclopent-1-enyl}-benzoic Acid

3-{2-[5-Bromo-2-(methoxy)-phenyl]-cyclopent-1-enyl}-benzoic acid ethylester (416 mg, 10.0 mmol) in dichloromethane (5 mL) was cooled undernitrogen to ˜40° C. and was treated with a molar solution ofborontribromide in dichloromethane (20 mL, 20.0 mmol). The reactionmixture was then allowed to reach room temperature and kept stirringover night. The reaction mixture was then quenched with ice/water (50/50mL) and more dichloromethane (30 mL) was added. After stirringvigorously for 1.5 hr. the organic layer was separated, dried (magnesiumsulphate), evaporated down and chromatographed with 1% methanol indichloromethane to give (300 mg, 80%).

¹H NMR (400 MHz, CDCl₃) 2.08-2.19 (2H, m), 2.82-2.90 (2H, m), 3.00-3.08(2H, m), 6.72 (1H, d, J=4 Hz), 7.24-7.40 (4H, m), 7.94 (1H, d, J=4 Hz),7.99 (1H, s).

LC/MS [MH−] 359 Rt=3.74 min.General Procedure 5

6-{2-[5-Chloro-2-(4-chloro-benzyloxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylicAcid 4-chloro-benzyl Ester

6-{2-[5-Chloro-2-(hydroxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylicacid (97 mg, 0.30 mmol) was refluxed in 2-butanone (4 mL) with4-chlorobenzyl bromide (140 mg, 0.70 mmol) and potassium carbonate (1.0g) under nitrogen for five hours. The reaction mixture was then filteredthrough highflo, evaporated down to an oil and chromatographed on aWater's sep-pak (10 g) with ether/iso-hexane (15/85) to give (160 mg,92%).

LC/MS [MH+] 556 Rt=5.5 min.

¹H NMR (400 MHz, CDCl₃) 2.03-2.12 (2H, m), 2.84-2.92 (2H, m), 3.06-3.14(2H, m), 4.85 (2H, s), 5.33 (2H, s), 6.76 (1H, d, J=8 Hz), 7.02-7.13(5H, m), 7.24-7.29 (2H, m), 7.32-7.40 (4H, m), 7.47 (1H, t, J=8 Hz),7.81 (1H, d, J=2 Hz).

6-{2-[5-Chloro-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylic4-fluorobenzyl Ester

Prepared according to general procedure 5.

Product (150 mg, 92%).

LC/MS (CF106348-1) [MH+] 532 Rt=4.27 min.

¹H NMR (400 MHz, CDCl₃) 2.02-2.11 (2H, m), 2.84-2.91 (2H, m), 3.06-3.13(2H, m), 4.86 (2H, s), 5.34 (2H, s), 6.78 (1H, d, J=8 Hz), 6.92-6.99(2H, m), 7.01-7.16 (7H, m), 7.40-7.50 (3H, m), 7.81 (1H, d, J=8 Hz).General Procedure 6

5-{2-[5-Chloro-2-(hydroxy)-phenyl]cyclopent-1-enyl}-nicotinic Acid EthylEster

5-{2-[5-Chloro-2-(methoxy)-phenyl]-cyclopent-1-enyl}-nicotinic acidethyl ester (1.500 g, 4.20 mmol) in dry dichloromethane (20 mL) wascooled to −75° C. Boron tribromide, 1M solution in DCM, (40 mL, 40.0mmol) was added and the reaction mixture stirred at −75° C. for afurther hour. The temperature of the reaction was then allowed to riseto −15° C. and kept at −15° C. for a further 2 hours, and was thenquenched in ice/water (50 g/50 mL). More dichloromethane (60 mL) wasadded and the resulting mixture was stirred vigorously for ˜2 hrs. Thelayers were separated and the organic layer was washed with saturatedsodium bicarbonate, dried (magnesium sulphate), filtered and reduced toan oil. The oil was then purified by chromatography to give the titlecompound (0.800 g, 60%).

LC/MS [MH+] 344 Rt=3.56.

¹NMR (400 MHz, CDCl₃) 1.38 (3H, t, J=7 Hz), 2.10-2.20 (2H, m), 2.86-2.95(2H, m), 2.96-3.05 (2H, m), 4.38 (2H, q, J=7 Hz), 6.74 (1H, d, J=8 Hz),7.03-7.12 (2H, m), 8.27 (1H, s), 8.53 (1H, s), 8.94 (1H, s).

5-{2-[5-Bromo-2-(hydroxy)-phenyl]-cyclopent-1-enyl}-nicotinic Acid EthylEster

Prepared by general procedure 6

-   5-{2-[5-Bromo-2-(methoxy)-phenyl]-cyclopent-1-enyl}-nicotinic acid    ethyl ester (1.100 g, 2.70 mol)-   dichloromethane (10 mL)-   boron tribromide (1 Molar solution in dichloromethane) (30 mL)-   product (0.53 g, 53%).

¹H NMR (400 MHz, CDCl₃) 1.39 (3H, q, J=7 Hz), 2.14-2.25 (2H, m),2.90-3.10 (4H, m), 4.43 (2H, q, J=7 Hz), 6.80 (1H, d, J=8 Hz), 6.93 (1H,d, J=8 Hz), 7.23-7.30 (1H, m), 8.60 (1H, s), 8.65 (1H, s), 8.93 (1H, s).

LC/MS [MH+] 390 Rt=3.58 min.

5-{2-[5-Trifluoromethyl-2-(hydroxy)-phenyl]cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared by general procedure 6

-   5-{2-[5-Trifluoromethyl-2-(methoxy)-phenyl]-cyclopent-1-enyl}-nicotinic    acid ethyl ester-   (0.500 g, 1.20 mmol)-   dichloromethane (10 mL)-   boron tribromide (1M solution in dichloromethane) (20 mL)-   product (0.480 g)

¹H NMR (400 MHz, CDCl₃) 1.36 (3H, t, J=7 Hz), 2.13-2.20 (2H, m),2.87-2.95 (2H, m), 2.97-3.07 (2H, m), 4.37 (2H, q, J=7 Hz), 6.70 (1H, d,J=8 Hz), 7.23-7.34 (2H, m), 8.17 (1H, s), 8.44 (1H, d, J=1.6 Hz), 8.95(1H, d, J=1.6 Hz).

LC/MS [MH+] 378 Rt=3.60 min.

6-{2-[5-Chloro-2-(hydroxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylicAcid Methyl Ester

prepared by general procedure 6

-   6-{2-[5-Chloro-2-(methoxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylic    acid methyl-   ester (0.700 g, ˜75% pure)-   dichloromethane (5 mL)-   borontribromide (1M in dichloromethane) (10 mL).    Two products isolated:-   6-{2-[5-Chloro-2-(hydroxy)-phenyl}cyclopent-1-enyl}-pyridine-2-carboxylic    acid methyl ester (0.200 g)

LC/MS [MH+] 330 Rt-3.45 min.

¹H NMR (400 MHz, CDCl₃) 2.07-2.17 (2H, m), 2.85-2.93 (2H, m), 3.02-3.09(2H, m), 3.97 (3H, s), 7.02 (1H, d, J=4.5 Hz), 7.06 (1H, d, J=1.5 Hz),7.14 (1H, dd, J=1.5 Hz, J=5.5 Hz), 7.49 (1H, d, J=4 Hz), 7.83 (1H, t,J=7.5 Hz), 7.94 (1H, d, J=4 Hz), 9.37 (1H, s).

-   6-{2-[5-Chloro-2-(hydroxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylic    acid (0.195 g)

LC/MS [MH+] 315 Rt=3.08 min

¹H NMR (400 MHz, CDCl₃) 2.12-2.22 (2H, m), 2.87-2.96 (2H, m), 3.05-3.13(2H, m), 6.95 (1H, d, J=9 Hz), 7.06 (1H, d, J=2.5 Hz), 7.18 (1H, dd, J=3Hz, J=1 Hz), 7.47 (1H, d, J=8 Hz), 7.87 (1H, t, J=8.5 Hz), 8.03 (1H, d,J=7 Hz).General Procedure 7

Example 3 3-{2-[5-bromo-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

3-{2-[5-Bromo-2-(hydroxy)-phenyl]-cyclopent-1-enyl}-benzoic acid (0.04g, 0.12 mmol), benzyl bromide (0.038 g, 0.22 moles), potassium hydroxide(˜0.15 g), in dimethyl sulphoxide (1.5 mL) were stirred at roomtemperature over 8 hrs under nitrogen. The reaction mixture was thenquenched with ice/water (10/10 mL), stirred at room temperature for ˜1.5hrs, acidified with 2N hydrochloric acid to pH˜3 and extracted withdichloromethane. The organic extract was then dried (magnesium sulphate)and concentrated down to an oil and was then chromatographed on Waterssep-pak cartridge (10 g) giving (0.028 g, 54%).

LC/MS [MH−] 449 Rt=4.19 min.

¹H NMR (400 MHz, CDCl₃) 2.03-2.12 (2H, m), 2.83-2.90 (2H, m), 2.91-2.97(2H, m), 4.94 (2H, s), 6.77 (1H, d, J=9 Hz), 7.14-7.23 (4H, m),7.23-7.34 (5H, m), 7.85 (1H, d J=7.5 Hz), 7.89 (1H, s).

Example 43-{2-[5-Bromo-2-(4-Chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

Prepared according to general procedure 7

Product (22 mg, 31%)

LC/MS (CF104431-1) [MH−] 483 Rt=4.36 min.

Example 53-{2-[5-Bromo-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

Prepared according to general procedure 7

Product (22 mg, 32%)

LC/MS [MH−] 467 Rt=4.19 min.

Example 63-{2-[5-Bromo-2-(3,4-dichlorobenzyloxy)-penyl]-cyclopent-1-enyl}-benzoicAcid

Prepared according to general procedure 7

Product (18 mg, 24%)

LC/MS [MH−] 517 Rt=4.53 min ˜60% pure

Example 73-{2-[5-Bromo-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

Prepared according to general procedure 7

Product (27 mg, 38%)

¹H NMR (400 MHz, CDCl₃) 2.03-2.12 (2H, m), 2.79-2.86 (2H, m), 2.90-2.97(2H, m), 4.92 (2H, s), 6.74-6.83 (3H, m), 7.08-7.28 (4H, m), 7.32 (1H,dd, J=3 Hz, J=11 Hz), 7.84-7.88 (2H, m).

Example 83-{2-[5-Bromo-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

Prepared according to general procedure 7

Product (19 mg, 26%)

LC/MS [MH−] 501 Rt=4.39 min.

¹H NMR (400 MHz, CDCl₃) 2.03-2.13 (2H, m), 2.79-2.87 (2H, m), 2.90-2.98(2H, m), 4.93 (2H, s), 6.77 (1H, d, J=8 Hz), 7.03-7.28 (6H, m), 7.31(1H, dd, J=3 Hz, J=10 Hz) 7.83-7.87 (2H, m).

Example 93-{2-[5-Bromo-2-(4-methoxybenzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

Prepared according to general procedure 7

Product (14 mg, 20%).

LC/MS [MH−] 479 Rt=4.15 min.General Procedure 8

5-{2-[5-Chloro-2-(4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

5-{2-[5-Chloro-2-(hydroxy)-phenyl]-cyclopent-1-enyl}-nicotinic acidethyl ester (138 mg, 0.43 mmol) was treated with 4 chlorobenzyl bromide(0.130 g, 60 mmol) and potassium carbonate (1.000 g) and 2-butanone (5mL) at reflux for 18 hrs. Upon cooling, the mixture was filtered throughhighflo and reduced down to an oil. The product was purified using aWater's sep-pak cartridge (10 g) to give (90 mg, 44%).

LC/MS [MH+] 468 Rt=4.19 min.

5-{2-[5-Chloro-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8

Product (80 mg, 41%)

LC/MS [MH+] 452 Rt=4.05 min.

¹H NMR (400 MHz, CDCl₃) 1.35 (3H, t, J=7Hz), 2.05-2.14 (2H, m), 2.82(2H, m), 2.89-2.96 (2H, m), 4.34 (2H, q, J=7 Hz), 4.86 (2H, s), 6.83(1H, d, J=9 Hz), 6.94-7.20 (6H, m), 7.94 (1H, t, J=8 Hz), 8.43 (1H, d,J=4 Hz), 8.92 (1H, d, J=4 Hz).

5-{2-[5-Chloro-2-(3,4-dichlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8

Product (10 mg, 45%)

LC/MS [MH+] 504 Rt=4.32 min.

5-{2-[5-Chloro-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8

Product (105 mg, 51%)

LC/MS [MH+] 470 Rt=4.07 min.

¹H NMR (400 MHz, CDCl₃) 1.36 (3H, t, J=7 Hz), 2.04-2.13 (2H, m),2.80-2.88 (2H, m), 2.88-2.96 (2H, m), 4.35 (2H, q, J=7 Hz), 4.92 (2H,s), 6.74-6.84 (2H, m), 6.87 (1H, d, J=9 Hz), 7.04 (1H, d, J=3 Hz),7.08-7.17 (1H, q, J=8 Hz), 7.19 (1H, dd, J=3.5 Hz, J=10 Hz), 7.94 (1H,t, J=4 Hz), 8.40 (1H, d, J=2 Hz), 8.92 (1H, d, J=2 Hz).

5{2-[5-Chloro-2-(4-chloro-2-fluorobenzyloxy)-phenyl}-cyclopent-1-enyl]-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8

Product (90 mg, 42%)

LC/MS [MH+] 486 Rt=4.20 min.

¹H NMR (400 MHz, CDCl₃) 1.35 (3H, t, J=7 Hz), 2.05-2.14 (2H, m),2.81-2.89 (2H, m), 2.89-2.97 (2H, m), 4.34 (2H, q, J=7 Hz), 4.93 (2H,s), 6.86 (1H, d, J=9 Hz), 7.02-7.12 (4H, m), 7.19 (1H, dd, J=3 Hz, J=11Hz), 7.95 (1H, t, J=4 Hz), 8.43 (1H, d, J=2 Hz), 8.92 (1H, d, J=1 Hz).

5-{2-[5-Chloro-2-(4-methoxybenzyloxy)-phenyl)]-cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8

Product (95 mg, 47%)

LC/MS [MH+] 464 Rt=4.02 min.

5-{2-[5-Bromo-2-(4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8

Product (16 mg, 16%)

LC/MS [MH+]514 Rt=4.22min

¹H NMR (CDCl₃) 1.36 (3H, t, J=7.5 Hz), 2.05-2.15 (2H, m), 2.82-2.89 (2H,m), 2.89-2.96 (2H, m), 4.30-4.39 (2H, q, J=7.5 Hz), 4.86 (2H, s), 6.76(1H, d, J=8 Hz), 7.08 (1H, d, J=7.5 Hz), 7.19 (1H, d, J=2 Hz), 7.23-7.34(4H, m), 7.95 (1H, s), 8.43 (1H, s), 8.92 (1H, s).

5-{2-[5-Bromo-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic AcidEthyl Ester

Prepared according to general procedure 8

Product (16 mg, 17%)

LC/MS [MH+] 480 Rt=4.09 min.

¹H NMR (400 MHz, CDCl₃) 1.34 (3H, t, J=8 Hz), 2.05-2.14 (2H, m),2.83-2.90 (2H, m), 2.90-2.97 (2H, m), 4.35 (2H, q, J=8 Hz), 4.92 (2H,s), 6.79 (1H, d, J=8 Hz), 7.14-7.20 (3H, m), 7.23-7.33 (4H, m), 7.90(1H, s), 8.45 (1H, s), 8.92 (1H, s).

5-{2-[5-Bromo-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8

Product (14 mg, 15%).

LC/MS [MH+] 498 Rt=4.09 min.

¹H NMR (400 MHz, CDCl₃) 1.36 (3H, t, J=7 Hz), 2.04-2.13 (2H, m),2.82-2.89 (2H, m), 2.89-2.96 (2H, m), 4.35 (2H, q, J=7 Hz), 4.86 (2H,s), 6.78 (1H, d, J=7.5 Hz), 6.98 (2H, t, J=7.5 Hz), 7.08-7.16 (2H, m),7.19 (1H, s), 7.31 (1H, d, J=9 Hz), 7.94 (1H, s), 8.44 (1H, s), 8.92(1H, s).

5-{2-[5-Bromo-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8

Product (44 mg, 44%)

LC/MS [MH+] 516 Rt=4.10 min.

¹H NMR (400 MHz, CDCl₃) 1.36 (3H, t, J=7 Hz), 2.03-2.13 (2H, m),2.80-2.88 (2H, m), 2.87-2.96 (2H, m), 4.34 (2H, q, J=7 Hz), 4.91 (2H,s), 7.74-6.85 (3H, m), 7.08-7.16 (1H, bq, J=7.5 Hz), 7.18 (1H, d, J=2Hz), 7.30-7.35 (1H, m), 7.95 (1H, s), 8.42 (1H, s), 8.92 (1H, s).

5-{2-[5-Bromo-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8

Product (41 mg, 41%).

LC/MS [MH+] 532 t=4.24 min.

¹H NMR (400 MHz, CDCl₃) 1.36 (3H, t, J=6.5 Hz), 2.05-2.14 (2H, m),2.80-2.89 (2H, m), 2.89-2.97 (2H, m), 4.36 (2H, m), 4.93 (2H, s), 6.80(1H, d, J=7 Hz), 7.03-7.21 (4H, m), 7.33 (1H, d, J=6.5 Hz), 7.95 (1H,s), 8.43 (1H, s), 8.92 (1H, s).

5-{2-[5-Bromo-2-(cyclohexylmethoxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8

Product (53 mg, 56%)

LC/MS [MH+] 486 Rt=4.47 min.

¹H NMR (400 MHz, CDCl₃) 0.89 (3H, m) 1.03-1.28 (4H, m), 1.36 (3H, t, J=7Hz), 1.50-1.72 (4H, m), 2.05-2.15 (2H, m), 2.79-2.88 (2H, m), 2.88-2.98(2H, m), 3.62 (2H, d, J=6 Hz), 4.35 (2H, q, J=7 Hz), 6.72 (1H, d, J=8Hz), 7.10 (1H, s), 7.28-7.33 (1H, m), 8.2 (1H, s), 8.45 (1H, s), 8.93(1H, s).

5-{2-[5-Trifluoromethyl-2-(4-Chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8

Product (19 mg, 14%).

¹H NMR (400 MHz, CDCl₃) 1.33 (3H, t, J=7 Hz), 2.08-2.17 (2H, m),2.86-2.98 (4H, m), 4.33 (2H, q, J=7 Hz), 4.93 (2H, s), 6.94 (1H, d,J=4.3 Hz), 7.09 (2H, d, J=8 Hz), 7.24-7.36 (3H, m), 7.48 (1H, dd, J=2Hz, J=10 Hz), 7.93 (1H, d, J=4 Hz), 8.41 (1H, d, J=2 Hz), 9.92 (1H, d,J=2 Hz).

5-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8

Product (29 mg, 22%)

LC/MS [MH+] 486 Rt=4.05 min.

¹H NMR (400 MHz, CDCl₃) 1.33 (3H, t, J=7 Hz), 2.06-2.16 (2H, m),2.80-2.98 (4H, m), 4.33 (2H, q, J=7.5 Hz), 4.92 (2H, s), 6.93-7.03 (3H,m), 7.10-7.16 (2H, m), 7.34 (1H, d, J=2 Hz), 7.49 (1H, dd, J=3 Hz), 7.92(1H, t, J=2 Hz), 8.40 (1H, d, J=2 Hz), 8.92 (1H, d, J=4 Hz).

5-{2-[5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8

Product (42 mg, 31%).

LC/MS [MH+] 504 Rt=4.07 min.

¹H NMR (400 MHz, CDCl₃) 1.33 (3H, t, J=7.2 Hz), 2.06-2.16 (2H, m),2.83-2.91 (2H, m), 2.91-2.98 (2H, m), 4.33 (2H, q, J=7 Hz), 4.99 (2H,s), 6.76-6.84 (2H, m), 7.01 (1H, d, J=9 Hz), 7.12 (1H, q, J=8 Hz), 7.33(1H, d, J=2 Hz), 7.51 (1H, dd, J=2 Hz, J=10 Hz), 7.92 (1H, t, J=4 Hz),8.40 (1H, d, J=2 Hz), 8.92 (1H, d, J=2 Hz).

5-{2-[5-Trifluoromethyl-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1enyl]-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8

Product (47 mg, 35%).

¹H NMR (400 MHz, CDCl₃) 1.33 (3H, t, J=7 Hz), 2.06-2.17 (2H, m),2.84-2.92 (2H, m), 2.92-2.99 (2H, m), 4.33 (2H, q, J=7 Hz), 5.00 (2H,s), 6.99 (1H, d, J=8 Hz), 7.04-7.12 (3H, m), 7.33 (1H, d, J=2 Hz), 7.51(1H, dd, J=3 Hz), 7.92 (1H, t, J=4 Hz), 8.41 (1H, d, J=2 Hz), 8.92 (1H,d, J=2 Hz).

5-{2-[5-Trifluoromethyl-2-(cyclohexylmethoxy)-phenyl]cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8

Product (46 mg, 36%)

LC/MS [MH+] 474 Rt=4.41 min.

6-{2-[5-Chloro-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylicAcid Methyl Ester

Prepared according to general procedure 8

Product (124 mg, 90%).

LC/MS [MH+] 456 Rt=4.01 min

¹H NMR (400 MHz, CDCl₃) 2.03-2.12 (2H, m), 2.83-2.90 (2H, m), 3.06-3.14(2H, m), 3.93 (3H, s), 4.93 (2H, s), 6.74-6.83 (2H, m), 6.85 (1H, d, J=9Hz), 7.01-7.08 (2H, m), 7.13-7.20 (2H, m), 7.48 (1H, t, J=8 Hz), 7.83(1H, d, J=8 Hz).

6-{2-[5-Chloro-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl-}pyridine-2-carboxylicAcid Methyl Ester

Prepared according to general procedure 8

Product (135 mg, 94%)

LC/MS (CF106321-1) [MH+] 472 Rt=4.15 min.

¹H NMR (400 MHz CDCl₃) 2.03-2.12 (2H, m), 2.84-2.9 (2H, m), 3.07-3.14(2H, m) 3.93 (3H, s), 4.93 (2H, s), 6.83 (1H, d, J=8 Hz), 7.01-7.15 (5H,m), 7.15-7.20 (1H, dd, J=3 Hz, J=11 Hz), 7.48 (1H, t, J=7.5 Hz), 7.83(1H, d, J=8 Hz).General Procedure 9: Ester Hydrolysis

Example 1 3-{2-[5-chloro-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

3-{2-[5-chloro-2-(benzyloxy)-phenyl)cyclopent-1-enyl]-benzoic acid ethylester (80 mg) was refluxed for 1 h in methanol/2N sodium hydroxide(10:10 mL). The reaction mixture was then evaporated down to 3 mL. 2NHydrochloric acid (10 mL) was added and the product extracted withdichloromethane (2×10 mL), dried (magnesium sulphate) and evaporated togive an oil which solidified on standing (70 mg).

LC/MS [MH−] 403 Rt=3.63 min

Example 2 3-[2-(2-Benzyloxy-phenyl)-cyclopent-1-enyl]-benzoic Acid

Prepared according to general procedure 9

Product (100 mg).

LC/MS [MH−] 369 Rt=3.81 min.

General Procedure 10

Example 105-{2-[5-Chloro-2-(4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

5-{2-[5-Chloro-2-(4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid ethyl ester (90 mg) was hydrolysed in methanol (3 mL) and 2N sodiumhydroxide (2 mL) at 60° C. with stirring for 2 hrs. The reaction mixturewas then reduced down to ˜1 mL, diluted with water (10 mL) and treatedwith a few drops of glacial acetic acid to make the solution ˜pH5. Theproduct was then extracted twice with dichloromethane (10 mL) dried(magnesium sulphate), and evaporated to give the title compound (75 mg).

LC/MS [MH+] 440 Rt=4.22 min.

Example 115-{2-[5-Chloro-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic Acid

Prepared according to general procedure 10

Product (95 mg, yield).

¹H NMR (400 MHz, CDCl₃) 2.06-2.16 (2H, m), 2.85-2.99 (4H, m), 4.93 (2H,s), 6.85 (1H, d, J=8 Hz), 7.4 (1H, d, J=3 Hz), 7.13-7.22 (3H, m),7.22-7.34 (3H, m), 8.65 (1H, t, J=4 Hz), 8.49 (1H, d, J=2 Hz), 9.01 (1H,d, J=2 Hz).

Example 125-{2-[5-Chloro-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

Prepared according to general procedure 10

-   (60 mg, 81%)

LC/MS [MH+] 424 Rt=3.99 min.

¹H NMR (400 MHz, CDCl₃) 2.06-2.16 (2H, m), 2.84-2.98 (4H, m), 4.86 (2H,s), 6.83 (1H, d, J=7.5 Hz), 6.99 (2H, t, J=7.5 Hz), 7.65 (1H, d, J=2Hz), 7.1-7.2 (3H, m), 8.05 (1H, s), 8.49 (1H, b.s), 9.02 (1H, b.s).

Example 135-{2-[5-Chloro-2-(3,4-dichlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

Prepared according to general procedure 10

Product (87 mg, 92%)

LC/MS [MH+] 476 Rt=4.43 min.

Example 145-{2-[5-Chloro-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

Prepared according to general procedure 10

Product (95 mg, 96%)

LC/MS [MH+] 442 Rt=4.00 min.

¹H NMR (400 MHz, CDCl₃) 2.50-2.15 (2H, m), 2.81-2.89 (2H, m), 2.89-2.98(2H, m), 4.92 (2H, s), 6.74-6.9 (3H, m), 7.05 (1H, d, J=2 Hz), 7.11-7.22(2H, m), 8.05 (1H, s), 8.47 (1H, s), 9.05 (1H, m).

Example 155-{2-[5-Chloro-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

Prepared according to general procedure 10

Product (75 mg, 89%).

LC/MS [MH+] 458 Rt=4.22 min.

¹H NMR (400 MHz, CDCl₃) 2.06-2.16 (2H, m), 2.83-2.91 (2H, m), 2.91-2.99(2H, m), 4.93 (2H, s), 6.86 (1H, d, J=8 Hz), 7.03-7.15 (4H, m), 7.18(1H, dd, J=3 Hz, J=9.5 Hz), 8.05 (1H,s), 8.48 (1H, d, J=2 Hz), 9.1(1H,s).

Example 165-{2-[5-Chloro-2-4-methoxybenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

Prepared according to general procedure 10

Product (78 mg, 87%).

LC/MS [MH+] 436 Rt=3.92 min.

Example 175-{2-[5-Bromo-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic Acid

Prepared according to general procedure 10

Product (11 mg, 73%).

LC/MS [MH+] 450 Rt=4.06 min

¹H NMR (400 MHz, CDCl₃) 2.06-2.15 (2H, m), 2.84-2.98 (4H, m), 4.93 (2H,s), 6.80 (1H, d, J=8 Hz), 7.15-7.21 (3H, m), 7.23-7.34 (4H, m), 8.05(1H, s), 8.49 (1H, s), 8.99 (1H, s).

Example 185-{2-[5-Bromo-2-(4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

Prepared according to general procedure 10

Product (40 mg, 70%)

LC/MS [MH+] 486 Rt=4.27 min.

¹NMR (400 MHz, CDCl₃) 2.06-2.16 (2H, m), 2.84-2.92 (2H, m), 2.92-2.98(2H, m), 4.86 (2H, s), 6.76 (1H, d, J=8 Hz), 7.10 (2H, d, J=8 Hz), 7.21(1H, s), 7.24-7.36 (3H, m), 8.03 (1H, s), 8.48 (1H, s), 8.99 (1H, s).

Example 195-{2-[5-bromo-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

Prepared according to general procedure 10

Product (19 mg, 76%)

LC/MS (CF105499-1) [MH+] 470 Rt=4.05 min

¹H NMR (400 MHz, CDCl₃) 2.06-2.15 (2H, m), 2.83-2.97 (4H, m), 4.86 (2H,s), 6.78 (1H, d, J=8 Hz), 6.98 (2H, t, J=7 Hz), 7.10-7.17 (2H, m), 7.20(1H, s), 7.31 (1H, dd, J=2 Hz, J=10 Hz), 8.02 (1H, s), 8.48 (1H, s),8.99 (1H, s).

Example 205-{2-[6-Bromo-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

Prepared according to general procedure 10

Product (3 mg, 73%)

LC/MS [MH+] 4.88 Rt-4.06 min.

¹H NMR (400 MHz, CDCl₃) 2.05-2.15 (2H, m), 2.81-2.90 (2H, m), 2.90-2.98(2H, m), 4.93 (2H, s), 6.76-6.87 (3H, m), 7.10-7.23 (2H, m), 7.3-7.36(1H, d, J=9 Hz), 8.04 (1H, s), 8.48 (1H, s), 9.00 (1H, s).

Example 215-{2-45-Bromo-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

Prepared according to general procedure 10

Product (3 mg, 80%)

LC/MS [MH+] 505 Rt=4.29 min.

¹H NMR (400 MHz, CDCl₃) 2.06-2.15 (2H, m), 2.82-2.90 (2H, m), 2.90-2.98(2H, m), 4.93 (2H, s), 6.81 (1H, d, J=8 Hz), 7.03-7.18 (3H, m), 7.19(1H, s), 7.33 (1H, d, J=8 Hz), 8.03 (1H, s), 8.47 (1H, s), 8.99 (1H, s).

Example 225-{2-[5-Bromo-2-(4-methoxybenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

Prepared according to general procedure 10

Product (12 mg, 92%)

LC/MS [MH+] 481 Rt=4.01 min.

¹H NMR (400 MHz, CDCl₃) 2.04-2.14 (2H, m), 2.83-2.96 (4H, m), 3.76 (3H,s), 4.83 (2H, s), 6.77-6.86 (3H, m), 7.08 (2H, d, J=8 Hz), 7.18 (1H, d,J=2.6 Hz), 7.30 (1H, dd, J=2 Hz, J=4 Hz), 8.02 (1H, s), 8.46 (1H, s),8.99 (1H, s).

Example 235-{2-[5-Bromo-2-(cyclohexylmethoxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

Prepared according to general procedure 10

Product (48 mg, 96%)

LC/MS [MH+] 458 Rt=4.60 min.

Example 245-{2-[5-Trifluoromethyl-2-(4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

Prepared according to general procedure 10

Product (16 mg, 89%)

LC/MS [MH+] 474 Rt=4.11 min.

¹H NMR (400 MHz, CDCl₃) 2.08-2.18 (2H, m), 2.86-2.99 (4H, m), 4.93 (2H,s), 6.95 (1H, d, J=8 Hz), 7.11 (2H, d, J=8 Hz), 7.23-7.37 (3H, m), 7.48(1H, dd, J=2 Hz, J=9 Hz), 8.1 (1H, s), 8.44 (1H, s), 8.97 (1H, s).

Example 255-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

Prepared according to general procedure 10

Product (22 mg, 81%)

LC/MS [MH+] 458 Rt=3.93 min.

¹H NMR (400 MHz, CDCl₃) 2.07-2.17 (2H, m), 2.87-2.90 (4H, m), 4.93 (2H,s) 6.93-7.04 (3H, m), 7.11-7.18 (2H, m), 7.35 (1H, s), 7.48 (1H, d, J=8Hz), 8.03 (1H, s), 8.4 (1H, s) (1H, s).

Example 265-{2-[5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

Prepared according to general procedure 910

Product (35 mg, 88%)

LC/MS [MH+] 476 Rt=3.95 min.

¹H NMR (400 MHz, CDCl₃) 1.70-1.83 (2H, m), 2.5-2.78 (4H, m), 4.88 (2H,s), 6.65-6.75 (2H, m), 6.81-6.88 (1H, m), 7.03-7.12 (2H, m), 7.38-7.35(1H, d, J=9 Hz), 7.86 (2H, s) 8.68 (1H, s).

Example 275-{2-[5-Trifluoromethyl-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicAcid

Prepared according to general procedure 10

Product (38 mg, 86%)

LC/MS [MH−] 490 Rt=4.11 min.

¹H NMR (400 MHz, CDCl₃) 2.07-2.17 (2H, m), 2.85-2.99 (4H, m), 5.10 (2H,s), 6.99 (1H, d, J=8 Hz), 7.05-7.16 (3H, m), 7.34 (1H, d, J=2 Hz),7.46-7.54 (1H, m), 8.04 (1H, s), 8.43 (1H, s), 8.96 (1H, s).

Example 285-{2-[5-Trifluoromethyl-2-(cyclohexylmethoxy)-phenyl]-cyclopent-1-enyl]-nicotinicAcid

Prepared according to general procedure 10

Product (37 mg, 86%)

LC/MS (CF105897-1) [MH+] 446.1 Rt=4.36 min.

Example 296-{2-[5-Chloro-2-(2,4-difluorobenzyloxy)-phenyl]cyclopent-1-enyl}-pyridine-2-carboxylicAcid

Prepared according to general procedure 10

Product (92 mg, 76%)

LC/MS [MH+] 442 Rt=3.84 min

¹H NMR (400 MHz, CDCl₃) 2.06-2.16 (2H, m), 2.84-2.92 (2H, m), 2.97-3.5(2H, m), 4.93 (2H, s), 6.71-6.78 (2H, m), 6.95 (1H, d, J=8 Hz) 7.05-7.13(2H, m), 7.23-7.30 (2H, m), 7.71 (1H, t, J=7.5 Hz), 7.91 (1H, d, J=8Hz).

Example 306-{2-[5-Chloro-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylicAcid

Prepared according to general procedure 10

Product (112 mg, 85%)

LC/MS [MH+] 458 Rt=4.02 min

¹H NMR (400 MHz, CDCl₃) 2.07-2.17 (2H, m), 2.85-2.92 (2H, m), 2.98-3.05(2H, m), 4.93 (2H, s), 6.93 (1H, d, J=8 Hz) 6.98-7.08 (3H, m), 7.11 (1H,d, J=3 Hz), 7.24-7.30 (2H, m), 7.72 (1H, t, J=8 Hz), 7.90 (1H, d, J=7Hz).

Example 316-{2-[5-Chloro-2-4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}pyridine2-carboxylic Acid

Prepared according to general procedure 10

Product (70.0 mg, 56%)

LC/MS [MH+] 440 Rt=3.99 min.

¹H NMR (400 MHz CDCl₃) 2.07-2.17 (2H, m), 2.87-2.93 (2H, m), 2.98-3.05(2H, m) 4.87 (2H, s), 6.89 (1H, d, J=8 Hz), 7.05 (1H, d, J=7.5 Hz), 7.1(1H, d, J=3 Hz), 7.20-7.35 (5H, m) 7.15 (1H, t, J=7.5 Hz), 7.91 (1H, d,J=7 Hz).

Example 326-{2-[5-chloro-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-pyridine2-carboxylic Acid

Prepared according to general procedure 10

Product (60 mg, 50%)

LC/MS [MH+] 424 Rt=3.80 min.

¹H NMR (400 MHz CDCl₃) 2.07-2.16 (2H, m), 2.86-2.93 (2H, m), 2.98-3.05(2H, m), 4.87 (2H, s), 6.87-6.97 (2H, m), 7.01-7.12 (4H, m), 7.21-7.37(2H, m), 7.71 (1H, t, J=7 Hz), 7.91 (1H, d, J=7.5 Hz).

Example 333-{2-[5-methylsulfonyl-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid a) 2-Methoxy-5-methylthiophenylboronic Acid

1.6M butyllithium in hexanes (3.5 ml, 5.6 mmol) was added dropwise to astirred solution of 2-bromo-4-methylthioanisole (1.165 g, 5 mmol) inanhydrous tetrahydrofuran (30 ml) at −100° C. under nitrogen and stirredfor 5 minutes then warmed to −78° C. for 1 hour. Triisopropyl borate(2.82 g, 15 mmol) was added dropwise and the mixture allowed to warm toroom temperature. Hydrochloric acid (30 ml, 30 mmol) were added and themixture stirred vigorously for 1 hour. The organic phase was separated,washed with brine, dried (MgSO₄), evaporated to dryness and the residuepurified on Biotage using ethyl acetate/iso-hexane (3:7) to yield thetitle compound as a white solid. (616 mg, 62%).

¹H NMR (CDCl₃) δ: 2.47 (3H, s), 3.91 (3H, s), 5.82 (2H, s), 6.87 (1H, d,J=8 Hz), 7.41 (1H, dd, J=8 Hz, 2 Hz), 7.81 (1H, d, J=2 Hz).

b) 3-{2-[5-methylsulfonyl-2-(methoxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid Ethyl Ester

A mixture of 2-methoxy-5-methylthiophenylboronic acid (594 mg, 3 mmol),3-(2-bromo-cyclopent-1-enyl)-benzoic acid ethyl ester (885 mg, 3 mmol),potassium carbonate (2.76 g, 20 mmol) andtetrakis(triphenylphosphine)palladium(0) (347 mg, 0.3 mmol) was stirredand heated in 1:1 toluene/ethanol (30 ml) at 90° C. under nitrogen for 4hours. After cooling the mixture was diluted with diethyl ether/waterand the organic phase dried (MgSO₄), evaporated to dryness and thereside purified on Biotage using ethyl acetate/iso-hexane (1:19) toyield the title compound as a white solid. (790 mg, 71%).

¹H NMR (CDCl₃) δ: 1.33 (3H, t, J=7 Hz), 2.09 (2H, m), 2.27 (3H, s), 2.87(2H, m), 2.96 (2H, m), 3.66 (3H, s), 4.32, (2H, q, J=7 Hz), 6.80-7.28(5H, m), 7.77-7.85 (2H, m).

LC/MS t=4.03, [MH+] 369.1.

c) 3-{2-[5-methylsulfonyl-2-(hydroxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

A mixture of sodium methanethiolate (700 mg, 10 mmol) and(3-{2-[5-methylsulfanyl-2-(methoxy-)-phenyl]-cyclopent-1-enyl}-benzoicacid ethyl ester (720 mg, 1.96 mmol) in dimethylformamide (15 ml) wasstirred and heated at 120° C. under nitrogen for 5 hours. After coolingthe mixture was diluted with diethyl ether/water and the aqueous phaseseparated and acidified with hydrochloric acid then extracted withdiethyl ether. The organic phase was dried (MgSO₄), evaporated todryness and the residue triturated with diethyl ether/iso-hexane toyield the title compound as a white solid, (437 mg, 68%).

¹H NMR (CDCl₃) δ: 2.14 (2H, m), 2.88 (2H, t, J=8 Hz), 3.05, (2H, J=8Hz), 4.90 (1H, brs), 6.78, (1H, d, J=7 Hz), 7.16-7.39 (4H, m), 7.92 (1H,d, J=8 Hz), 7.99 (1H, s).

LC/MS t=3.54, [MH−] 325.

Standard Alkylation Procedure

d)3-{2-[5-methylsulfonyl-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid Benzyl Ester

A stirred mixture of 3-{2-[5-methylsulfonyl-2-(hydroxy)--phenyl]-cyclopent-1-enyl}-benzoic acid (65 mg, 0.2 mmol), potassiumcarbonate (138 mg, 1 mmol) and benzyl bromide (75 mg, 0.44 mmol) inacetone (4 ml) was refluxed for 16 hours then cooled and diluted withdiethyl ether/water. The organic phase was dried (MgSO₄), evaporated todryness and purified using Biotage with ethyl acetate/iso-hexane (1:19)to yield the title compound as a colourless gum. (85 mg, 84%).

¹H NMR (CDCl₃) δ: 2.06 (2H, m), 2.24 (3H, s), 2.90 (4H, m), 4.92 (2H,s), 5.28 (2H, s), 6.78 (1H, d, J=9 Hz), 6.97, d, J=2 Hz), 7.09-7.38(13H, m), 7.81 (1H, d, J=8 Hz), 7.86 (1H, s).

LC/MS t=4.43, [MH+] 507.1.

Standard Hydrolysis Procedure

e)3-{2-[5-methylsulfonyl-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

A solution of3-{2-[5-methylsulfonyl-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid benzyl ester (30 mg, 0.059 mmol) in ethanol (5 ml) and 2M sodiumhydroxide (1 ml) was left at room temperature for 20 hours then dilutedwith water, washed with ether and the aqueous phase separated, acidifiedwith 2M hydrochloric acid and extracted with ether. The organic extractwas dried (MgSO₄), evaporated to dryness and the residue triturated withiso-hexane to yield the title compound as a white solid. (14 mg, 57%).

¹H NMR (CDCl₃) δ: 2.08 (2H, m), 2.28, (3H, s), 2.92 (4H, m), 4.97 (2H,s), 6.85 (1H, d, J=9 Hz), 7.00 (1H, d, J=2 Hz), 7.14-7.33 (8H, m), 7.83(1H, d, J=8 Hz), 7.91 (1H, s).

LC/MS t=4.07, [MH−] 415.1.

Example 343-{2-[5-methylsulfonyl-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

Standard Oxidation Procedure

a)3-{2-[5-methanesulfonyl-2-(benzyloxy)-Phenyl]-cyclopent-1-enyl}-benzoicAcid Benzyl Ester

3-Chloroperbenzoic acid (53 mg, 0.236 mmol) was added to a solution of3-{2-[5-methylsulfonyl 2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid benzyl ester (51 mg, 0.1 mmol) in dichloromethane (4 ml) and leftat room temperature for 2.5 hours. The resulting solution was dilutedwith ether and washed with sodium thisulphate solution and sodiumbicarbonate solution then dried (MgSO₄), evaporated to dryness and theresidue purified using Biotage with ethyl acetate/iso-hexane (1:4) toyield the title compound as a colourless gum. (31 mg, 58%).

¹H NMR (CDCl₃) δ: 2.08 (2H, m), 2.72 (3H, s), 2.91 (4H, m), 5.04 (2H,s), 5.25 (2H, s), 6.93 (1H, d, J=9 Hz), 7.21-7.39 (12H, m), 7.52 (1-H,d, J=2 Hz), 7.68 (1H, dd, J=9 Hz, 2 Hz), 7.74 (1H, s), 7.81 (1H, d, J=8Hz).

b)3-{2-[5-methanesulfonyl-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

Prepared from3-{2-[5-methanesulfonyl-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid benzyl ester using the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.11 (2H, m), 2.84, (3H, s), 2.92 (4H, m), 5.09 (2H,s), 7.03 (1H, d, J=8 Hz), 7.21-7.35 (7H, m), 7.60 (1H, d, J=2 Hz),7.76-7.84 (3H, m).

LC/MS t=3.56 [MH−] 447.1.

Using the standard alkylation, hydrolysis and oxidation procedures thefollowing compounds were prepared:

Example 353-{2-[5-methylsulfanyl-2-4-fluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid a)3-{2-[5-methylsulfonyl-2-(4-fluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid 4-fluoro-benzyl Ester

¹H NMR (CDCl₃) δ: 2.05 (2H, m), 2.26 (3H, s), 2.85 (2H, t, J=8 Hz), 2.93(2H, t, J=8 Hz), 4.85 (2H, s), 5.24 (2H, s), 6.77 (1H, d, J=8 Hz),6.95-7.35 (12H, m), 7.77-7.82 (2H, m).

LC/MS t=4.42, [MH+] 543.1.

b)3-{2-[5-methylsulfonyl-2-(4-fluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

¹H NMR (CDCl₃) δ: 2.07 (2H, m), 2.30 (3H, s), 2.87 (2H, t, J=8 Hz), 2.94(2H, t, J=8 Hz), 4.90 (2H, s), 6.83 (1H, d, J=9 Hz). 6.97-7.02 (3H, m),7.14-7.28 (5H, m), 7.83 (1H, d, J=8 Hz), 7.89 (1H, s).

LC/MS t=4.06, [MH−] 433.

Example 363-{2-[5-methanesulfonyl-2-(4-fluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid a)3-{2-[5-methanesulfonyl-2-(4-fluoro-benzyloxy)-phenyl}-cyclopent-1-enyl]-benzoicAcid 4-fluoro-benzyl Ester

¹H NMR (CDCl₃) δ: 2.06 (2H, m), 2.80 (3H, s), 2.85-2.94 (4H, m) 4.97(2H, s), 5.23 (2H, s), 6.94-7.35 (8H, m), 7.57 (2H, m), 7.72-7.80 (3H,m), 7.97 (1H, d), 8.08 (1H, s).

b)3-{2-[5-methanesulfonyl-2-(4-fluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

¹H NMR (CDCl₃) δ: 2.10 (2H, m), 2.87 (3H, s), 2.87-2.98 (4H, m), 5.02(2H, s), 6.99-7.02 (3H, m), 7.16-7.28 (4H, m), 7.62 (1H, d, J=2 Hz),7.78-7.84 (3H, m).

LC/MS t=3.57, [MH−] 465.1.

Example 373-{2-[5-methylsulfonyl-2-(2,4-difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid a)3-{2-[5-methylsulfonyl-2-(2,4-difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid Benzyl Ester

¹H NMR (CDCl₃) δ: 2.06 (2H, m), 2.27 (3H, s), 2.84 (2H, t, J=8 Hz), 2.91(2H, t, J=8 Hz), 4.91 (2H, s), 5.30 (2H, s), 6.74-6.89 (5H, m), 6.98(1H, d, J=2 Hz), 7.11-7.26 (4H, m), 7.37 (1H, q, J=7 Hz), 7.76-7.79 (2H,m).

LC/MS t=4.46, [MH+] 579.1.

b)3-{2-[5-methylsulfonyl-2-(2,4-difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

¹H NMR (CDCl₃) δ: 2.07 (2H, m), 2.30 (3H, s), 2.86 (2H, t, J=8 Hz), 2.94(2H, t, J=8 Hz), 4.95 (2H, s), 6.76-6.88 (2H, m), 7.02 (1H, d, J=2 Hz),7.14-7.26 (4H, m), 7.82 (1H, d, J=8 Hz), 7.87 (1H, s).

LC/MS t=4.09, [MH−] 451.1.

Example 383-{2-[5-methanesulfonyl-2-(2,4-difluoro-benzyloxy)-phenyl-cyclopent-1-enyl}-benzoicacid a)3-{2-[5-methanesulfonyl-2-(2,4-difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid Benzyl Ester

¹H NMR (CDCl₃) δ: 2.07 (2H, m), 2.81 (3H, s), 2.85 (2H, t, J=8 Hz), 2.91(2H, t, J=8 Hz), 5.03 (2H, s), 5.28 (2H, s), 6.80-6.90 (4H, m), 6.99(1H, d, J=7 Hz), 7.08-7.21 (3H, m), 7.34-7.44 (1H, m), 7.55-7.61 (1H,m), 7.75-8.10 (3H, m).

b)3-{2-[5-methanesulfonyl-2-(2,4-difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

¹H NMR (CDCl₃) δ: 2.09 (2H, m), 2.88 (3H, s), 2.85-2.96 (4H, m), 5.07(2H, s), 6.80-6.84 (2H, m), 7.06 (1H, d, J=8 Hz), 7.12-7.26 (3H, m),7.62 (1H, d, J=2 Hz), 7.76 (1H, s), 7.80-7.84 (2H, m).

LC/MS t=3.59, [MH−] 483.

Example 2 3-{2-[(2-Benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic Acid a)3-[2-(2-Methoxy-phenyl)-cyclopent-1-enyl]-benzoic Acid Ethyl Ester

A mixture of 2-methoxyphenylboronic acid (510 mg, 3.36 mmol),3-(2-bromo-cyclopent-1-enyl)-benzoic acid ethyl ester (840 mg, 2.85mmol), potassium carbonate (3.18 g, 23.04 mmol) andtetrakis(triphenylphosphine)palladium(0) (370 mg, 0.32 mmol) was stirredand heated in 1:1 toluene/ethanol (30 ml) at 90° C. under nitrogen for 4hours. After cooling the mixture was diluted with diethyl ether/waterand the organic phase dried (MgSO₄), evaporated to dryness and theresidue purified on Biotage using ethyl acetate/iso-hexane (1:19) toyield the title compound as a colourless gum. (615 mg, 67%).

¹H NMR (CDCl₃) δ: 1.32 (3H, t, J=7 Hz), 2.09 (2H, m), 2.86 (2H, t, J=8Hz), 2.95 (2H, t, J=8 Hz), 3.68 (3H, s), 4.29 (2H, q, J=7 Hz), 6.82-7.26(6H, m), 7.76 (1H, d, J=8 Hz), 7.84 (1H,s).

b) 3-{2-[2-(Hydroxy)-phenyl]-cyclopent-1-enyl}-benzoic Acid

3-[2-(2-Methoxy-phenyl)-cyclopent-1-enyl]-benzoic acid ethyl ester (610mg, 1.89 mmol) was dissolved in 1M boron tribromide in dichloromethanesolution (18.9 ml, 18.9 mmol) and left at room temperature for 18 hours.The resulting solution was poured onto ice and extracted withdichloromethane. The organic extract was dried (MgSO₄), evaporated todryness and purified by chromatography using biotage with iso-hexanecontaining a gradient of ethyl acetate (20-40%) to yield the titlecompound as a light brown solid. (186 mg, 35%).

¹H NMR (CDCl₃) δ: 2.14 (2H, m), 2.89 (2H, t, J=8 Hz), 3.05 (2H, t, J=8Hz), 4.9 (1H, br s), 6.84 (1H, d, J=8 Hz), 6.93 (1H, t, J=7 Hz),7.18-7.38 (4H, m), 7.91 (1H, d, J=8 Hz), 7.99 (1H s).

LC/MS t=3.44, [MH−] 279.

Using the standard alkylation and hydrolysis procedures the followingcompounds were prepared.

c) 3-{2-[2-(Benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic Acid BenzylEster

¹H NMR (CDCl₃) δ: 2.06 (2H, m), 2.90 (4H, m), 4.94 (2H, s), 5.27 (2H,s), 6.80-6.87 (2H, m), 7.00 (1H, d, J=2 Hz), 7.13-7.36 (12H, m), 7.79(1H, d, J=8 Hz), 7.85 (1H, s).

LC/MS t=4.37, [MH+] 443.1.

d) 3-{2-[2-(Benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic Acid

¹H NMR (CDCl₃) δ: 2.08 (2H, m), 2.92 (4H, m), 5.00 (2H, s), 6.88 (1H, t,J=8 Hz), 6.92 (1H, d, 8 Hz), 7.02 (1H, dd, J=8 Hz, 2 Hz), 7.16-7.31 (8H,m), 7.81 (1H, d, J=8 Hz), 7.91 (1H, s).

LC/MS t=3.98, [MH−]369.1.

Examples 39 to 41 were prepared using the standard alkylation andhydrolysis procedures.

Example 393-{2-[2-(2,4-Difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic Acida) 3-{2-[2-(2,4-Difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid 2,4-difluoro-benzyl Ester

¹H NMR (CDCl₃) δ: 2.05 (2H, m), 2.85 (2H, t, J=8 Hz), 2.91 (2H, t, J=8Hz), 4.94 (2H, s), 5.28 (2H, s), 6.74-7.37 (15H, m), 7.76 (1H, d, J=8Hz), 7.79 (1H, s).

b) 3-{2-[2-(2,4-Difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

¹H NMR (CDCl₃) δ: 2.07 (2H, m), 2.87 (2H, t, J=8 Hz), 2.94 (2H, t, J=8Hz), 4.99 (2H, s), 6.76-6.82 (2H, m), 6.87-6.95 (2H, m), 7.04 (1H, dd,J=8 Hz, 2 Hz) 7.14-7.26 (4H, m) 7.81 (1H, d, J=8 Hz), 7.87 (1H,s).

LC/MS t=4.02, [MH−] 405.1.

Example 403-{2-[2-(4-chloro-2-fluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid a)3-{2-[2-(4-Chloro-2-fluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid 4-chloro-2-fluoro-benzyl Ester

¹H NMR (CDCl₃) δ: 2.06 (2H, m), 2.85 (2H, t, J=8 Hz), 2.92 (2H, t,J=8Hz), 4.95 (2H, s), 5.29 (2H, s), 6.86 (2H, m), 7.01-7.30 (10H, m),7.75-7.79 (2H, m).

b)3-{2-[2-(4-Chloro-2-fluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

¹H NMR (CDCl₃) δ: 2.08 (2H, m), 2.87 (2H, t, J=8 Hz), 2.95 (2H, t, J=8Hz), 4.99 (2H, s), 6.88-6.92 (2H, m), 7.04-7.07 (3H, m), 7.14-7.26 (4H,m) 7.81 (1H, d, J=8 Hz), 7.86 (1H,s).

LC/MS t=4.21, [MH−] 421.0, 422.9.

Example 413-{2-[2-4-Methoxy-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic Acid a)3-{2-[2-(4-Methoxy-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic Acid4-methoxy-benzyl Ester

¹H NMR (CDCl₃) δ: 2.04 (2H, m), 2.88 (4H, m) 3.78 (3H, s), 3.82 (3H, s),4.87 (2H, s), 5.20 (2H, s), 6.79-6.98 (7H, m), 7.11-7.32 (7H, m), 7.77(1H, d, J=8 Hz), 7.83 (1H,s).

b) 3-{2-[2-(4-Methoxy-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic Acid

¹H NMR (CDCl₃) δ: 2.06 (2H, m), 2.91 (4H, m), 3.79 (3H, s), 4.92 (2H,s), 6.82-6.87 (2H, m), 6.93 (1H, d, J=8 Hz), 7.01 (1H, dd, J=8 Hz, 2Hz)) 7.13-7.26 (6H, m), 7.81 (1H, d, J=8 Hz), 7.89 (1H,s).

LC/MS t=3.94, [MH−] 399.1.

Example 42 3-{2-[5-cyano-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid a) 5-Cyano-2-methoxyphenylboronic Acid

This compound was prepared in a similar manner to that described for2-methoxy-5-methylthio phenylboronic acid.

¹H NMR (DMSO-d₆) δ: 3.85 (3H,s), 7.13 (1H, d, J=9 Hz), 7.78 (1H, d, J=2Hz), 7.84 (1H, dd, J=8 Hz, 2 Hz) 8.03 (2H, br s).

LC/MS t=2.13, [MH+] 178.

b) 3-{2-[5-Cyano-2-(methoxy)-phenyl]-cyclopent-1-enyl}-benzoic Add EthylEster

This compound was prepared in a similar manner to that described for3-{2-[5-methylsulfonyl-2-(methoxy)-phenyl]-cyclopent-1-enyl}-benzoicacid ethyl ester.

¹H NMR (CDCl₃) δ: 1.34 (3H, t, J=7 Hz), 2.10 (2H, m), 2.82 (2H, t, J=7Hz), 2.96 (2H, t, J=7 Hz), 3.72 (3H, s), 4.31, (2H, q, J=7 Hz), 6.90 (1Hd, J=9 Hz), 7.17-7.28 (3H, m) 7.53 (1H, d, J=9 Hz), 7.77 (1H, s), 7.81(1H, d, J=7Hz)

c) 3-{2-[5-Cyano-2-(hydroxy)-phenyl]-cyclopent-1-enyl}-benzoic Acid

This compound was prepared in a similar manner to that described for3-[2-(2-hydroxy-phenyl)-cyclopent-1-enyl]-benzoic acid.

¹H NMR (CDCl₃) δ: 2.17 (2H, m), 2.88 (2H, t, J=8 Hz), 3.06 (2H, t, J=8Hz), 5.6 (1H, br s), 6.89 (1H, d, J=8 Hz), 7.28-7.36 (2H, m), 7.48 (1H,dd, J=8 Hz, 2 Hz), 7.53 (1H, d, J=2 Hz), 7.94 (2H, m).

LC/MS t=3.36, [MH−] 304.1

d) 3-{2-[5-cyano-2-(benzyloxy)-phenyl]-cyclopent-1-enyl-benzoic Acid

Prepared using the standard alkylation and hydrolysis procedures.

¹H NMR (CDCl₃) δ: 2.08 (2H, m), 2.86 (2H, t, J=8 Hz), 2.93 (2H, t, J=8Hz), 5.03 (2H,s), 5.6 (1H, brs) 6.9 (1H, d, J=8 Hz), 7.15-7.5 (9H, m),7.8-8.0 (2H, m).

LC/MS t=3.81, [MH−] 394.1

Example 433-{2-[5-cyano-2-(2,4-difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicAcid

Prepared using the standard alkylation and hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.08 (2H, m), 2.83 (2H, t, 8 Hz), 2.94 (2H, t, J=8Hz), 5.02 (2H,s), 5.8 (1H, br s) 6.82-6.84 (2H, m), 6.97 (1H, d, J=8Hz), 7.1-7.5 (4H, m), 7.79 (1H, s), 7.86 (1H, m).

LC/MS t=3.84, [MH−] 430.1.General Procedure A

A(i) 4-(Benzyloxy)benzotrifluoride

A solution of 4-hydroxybenzotrifluoride (8.55 g, 52.78 mmol) in acetone(200 ml) was treated with benzyl bromide (9.87 g, 6.86 m], 58.05 mmol)and potassium carbonate (10.94 g, 79.16 mmol). The mixture was stirredand heated to reflux under nitrogen for 3 h. After cooling, diethylether (400 ml) and water (400 ml) were added and the aqueous phasere-extracted with diethyl ether (100 ml). The combined organic layerswere washed with water, dried (MgSO₄) and the solvent removed in vacuoto leave the title compound as a white solid. (12.71 g, 95%)

¹H NMR (CDCl₃) δ 5.11 (2H,s), 7.03 (2H, d, J=9 Hz), 7.34-7.44 (5H, m),7.55 (2H, d, J=9 Hz).

A(ii) 2-Benzyloxy-5-(trifluoromethyl)iodobenzene

A solution of 4-(benzyloxy)benzotrifluoride (12.71 g, 50.4 mmol) inacetonitrile (300 ml) was stirred under nitrogen and1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (17.75 g, 50.4 mmol) and iodine (6.4 g, 25.2mmol) added. The mixture was stirred at room temperature for 88 h. Thesolvent was evaporated and the residue partitioned between ethyl acetate(400 ml) and water (400 ml). The organic layer was washed with water,dried (MgSO₄) and evaporated to an orange oil which was purified byflash chromatography (silica gel, 5% ethyl acetate: isohexane) to givethe title compound as an orange oil (15.07 g, 79%)

¹H NMR (CDCl₃) δ: 5.21 (2H, s), 6.89 (1H, d J=9 Hz), 7.32-7.55 (6H, m),8.04 (1H, d, J=2 Hz).

A(iii) 2-Benzyloxy-5-trifluoromethyl)benzeneboronic Acid

A solution of 4-benzyloxy-3-iodobenzotrifluoride (15.07 g, 39.85 mmol)in tetrahydrofuran (200 ml) was cooled to −40° C. with stirring undernitrogen. 2M isopropylmagnesium chloride in diethyl ether (39.85 ml,79.7 mmol) was added dropwise and the mixture stirred at −40° C. for 40minutes, then cooled to −75° C. Trimethyl borate (8.3 g, 9.2 m[, 79.7mmol) was added at −75° C. over 10 minutes and the reaction stirred andallowed to reach 0° C. over 1 h. 1M hydrochloric acid (200 ml) was addedand the mixture stirred vigorously for 1 h. The layers were separatedand the aqueous layer extracted with diethyl ether (100 ml). Thecombined organic layers were washed with water, dried (MgSO₄) andevaporated. The residue was flash chromatographed (silica gel, 5-20%ethyl acetate: isohexane) to give the title compound as a white solid.(7.71 g, 65%).

¹H NMR (CDCl₃) δ: 5.20 (2H, s), 5.79 (2H, s), 7.05 (1H, d, J=9 Hz),7.39-7.44 (5H, m), 7.68 (1H, dd J=2 Hz, J=9 Hz), 8.15 (1H, d, J=2 Hz).General Procedure 1

1(a(i)) 3-(2-Bromocyclopent-1-enyl}-benzoic Acid Ethyl Ester

1,2-Dibromocyclopentene (5.0 g, 22.1 mmol), (3-ethoxycarbonylphenyl)boronic acid (Combiblocks) (4.260 g, 22.1 mmol),tetrakistriphenylphosphinepalladium(0) (0.500 g) and potassium carbonate(5.0 g) were stirred at 80° C. under nitrogen for 18 h indimethoxyethane (30 mL). The reaction mixture was then filtered throughKieselguhr and evaporated down to give an oil.

Purification by chromatography using iso-hexane containing a gradient ofdichloromethane (0-30%) gave the required product (1.150 g, 30% yield).

1(a(ii)) 3-amino-5-(2-bromo-cyclopent-1-enyl)-benzoic Acid Methyl Ester

(3-amino-5-methoxycarbonylphenyl)boronic acid (2.66 g, 13.6 mmol), Pd(0)[PPh3]₄ (1.57 g, 1.36 mmol), potassium carbonate (15 g, 108 mmol) and1,2-dibromocyclopentene (12 g, 53 mmol) in toluene-ethanol (1:1 60 mL)were stirred at 90° C., under nitrogen, for 2 hrs. Upon cooling, thereaction mixture was poured into water and extracted with ethyl acetate(40×3 mL). The combined organic layers were dried over MgSO₄ andconcentrated. Purification was carried out on a Biotage® using isohexanecontaining a gradient of ethyl acetate (0-20%) to give the requiredproduct as yellow solid (3.5 g, 87%).

¹H NMR (CDCl₃): 1.96-2.0 (2H,m), 2.50 (2H,t,J=7.4), 2.67 (2H,t,J=7.4),3.80 (2H,bs), 3.88 (3H,s), 7.14 (1H,s), 7.28 (1H,s), 7.59 (1H,s).

LC/MS[MH+]=296, 298 Rt=3.38.

I(b) 3-[2-(2-Benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-benzoic AcidEthyl Ester

3-(2-Bromocyclopent-1-enyl)-benzoic acid ethyl ester (148 mg, 0.5 mmol),tetrakis(triphenylphosphine)palladium (0) (30 mg), potassium carbonate(0.20 g) and (2-benzyloxy-5-chlorophenyl) boronic acid (150 mg, 0.5mmol) in dimethoxyethane (5 mL) were refluxed for 17 h under nitrogen.The reaction mixture was then filtered through Kieselghur and evaporateddown to an oil. Purification was carried out on a Water's separationpack (10 g) with dichloromethane/iso-hexane to give the product (85 mg).

LC/MS [MH+] 433 Rt=4.21 min.

¹H NMR (400 MHz, CDCl₃) 1.31 (3H, t, J=7 Hz), 2.01-2.12 (2H, m),2.81-2.88 (4H, m), 4.28 (2H, q, J=7 Hz), 4.93 (2H, s), 6.81 (1H, d, J=9Hz), 7.02 (1H, J=2 Hz), 7.10-7.33 (8H, m), 7.76-7.86 (2H, m).General Procedure B

General Procedure B(i)2-bromocyclopent-1-enylboronic Acid

1,2-dibromocyclopentene (10.1 g, 0.044 mol) was dissolved in 100 mL oftetrahydrofuran, cooled to −78° C. and n-butyllithium, 1.6 M solution inhexane (28 mL, 0.044 mol), was added dropwise over 20 minutes undernitrogen. The mixture was stirred at −78° C. for further 20 minutes,then triisopropylborate (20.8 mL, 0.089 mol) was added dropwise. Thecooling bath was then removed and the reaction mixture was allowed toreach room temperature. The reaction mixture was then quenched with 1MHCl (40 mL) and stirred vigorously at room temperature for 15 minutes.The organic layer was then separated, dried over magnesium sulphate andevaporated down. The residue was triturated with dichloromethane toyield the title compound as a white solid (2.2 g, 26%).

¹H NMR (CD₃OD): 1.92-1.98 (2H, m), 2.50-2.55 (2H, m), 2.73-2.78 (2H, m),5.02 (2H,s).

General Procedure B(ii)

3-(2-bromo-cyclopent-1-enyl)-6-methylbenzoic Acid Ethyl Ester

a) A solution of 5-amino-2-methylbenzoic acid ethyl ester (500 mg, 2.8mmol) and iodine (425 mg, 1.68 mmol) in toluene (20 ml) was cooled to 0°C. and treated with t-butyl nitrite (303 mg, 2.94 mmol). The reactionmixture was stirred at 0° C. for 1 hour then at room temperature overthe weekend. The reaction mixture was washed with 10% aq sodiumthiosulphate (20 ml), and brine (20 ml), dried and evaporated. Flashchromatography [silica, iso-hexane/EtOAc, 9:1] gave5-iodo-2-methylbenzoic acid ethyl ester as a brown oil 510 mg 63%.

¹H NMR (CDCl₃): 1.39 (3H, t, J=12 Hz), 2.53 (3H, s), 4.36 (2H, q, J=12Hz), 6.97 (1H, d, J=12 Hz), 7.37 (1H, d, J=12 Hz), 8.20 (1H, s).

b) 5-iodo-2-methyl-benzoic acid ethyl ester (500 mg, 1.72 mmol),2-bromo-cyclopent-1-enylboronic acid (330 mg, 1.72 mmol), potassiumcarbonate (1.9 g, 13.8 mmol), Pd(0)[PPh₃]₄ (100 mg, 0.086 mmol) intoluene-ethanol (1:1 60 mL) were stirred at 90° C., under nitrogen, for4 hrs. Upon cooling, the reaction mixture was poured into water andextracted with ether (50 mL). The organic layers was dried (MgSO₄),filtered and concentrated. Purification was carried out on a Biotage®using 20% of ethyl acetate in iso-hexane to give the required product asyellow oil (390 mg, 73%).

¹HNMR (CDCl₃): 1.39 (3H, t, J=12 Hz), 2.01-2.08 (2H, m), 2.59 (3H, s),2.77 (2H,m), 2.85 (2H, m), 4.36 (2H, q,J=12 Hz), 7.24 (1H, t, J=12 Hz),7.65 (1H, d, J=12 Hz), 8.12 (1H, s).

General Procedure B(iii)

5-{2-[5-chloro-2-benzyloxyphenyl]cyclopenten-1-enyl}-2-methylbenzoicAcid Ethyl Ester

(5-chloro-2-benzyloxyphenyl)boronic acid (150 mg, 0.5 mmol), Pd(0)[PPh₃b(25 mg, 0.021 mmol), potassium carbonate (483 mg, 3.36 mmol) and(3-(2-bromo-cyclopent-1-enyl)-6-methylbenzoic acid ethyl ester (130 mg,0.42 mmol) in toluene-ethanol (1:1 10 mL) were stirred at 90° C., undernitrogen, for 2 hrs. Upon cooling, the reaction mixture was poured intowater and extracted with ethyl acetate (3×20 mL). The combined organiclayers were dried (MgSO₄), filters and concentrated. The residue waspurified on a Biotage® using 5% of ethyl acetate in iso-hexane to givethe required product as white solid (114 mg, 61%).

¹HNMR (CDCl₃): 1.27 (3H,t, J=12 Hz), 2.01-2.08 (2H, m), 2.51 (3H, s),2.83 (2H, t, J=6 Hz), 2.90 (2H, t, J=6 Hz), 4.94 (2H, s), 6.80 (1H, d,J=Hz), 6.97-7.70 (9H, m), 7.70 (1H, s).

LC/MS; Rt=4.22 [M+H] 447 (1 Cl)General Procedure C

General Procedure C(i)

1-Bromo-2-(2-benzyloxy-5-chlorophenyl)cyclopentene

A mixture of 1,2-dibromocyclopentene (1.72 g, 7.6 mmol),2-benzyloxy-5-chlorophenylboronic acid (500 mg, 1.9 mmol), potassiumcarbonate (2.1 g, 15.2 mmol) and tetrakis (triphenylphosphine)palladium(0) (220 mg, 0.19 mmol) was stirred and heated in 1:1toluene/ethanol (15 ml) at 90° C. under nitrogen for 2 hours. Aftercooling the mixture was diluted with diethyl ether/water and the organicphase dried (magnesium sulphate), evaporated to dryness and the residuepurified by chromatography on silica (2% ethyl acetate in iso-hexanethen 10% dichloromethane in iso-hexane) to yield the title compound as awhite solid (427 mg, 62%).

¹H NMR (CDCl₃) δ: 1.99-2.07 (2H, m), 2.67-2.72 (2H, m), 2.76-2.81 (2H,m), 5.06 (2H, s), 6.85 (1H, d, J=9 Hz), 7.17-7.38 (7H, m).

General Procedure C(ii)

2-(2-Benzyloxy-5-chlorophenyl)cyclopentene-1-boronic Acid

A solution of n-butyllithium (0.73 ml, 1.6M in hexanes, 1.17 mmol) wasadded to a solution of1-bromo-2-(2-benzyloxy-5-chlorophenyl)cyclopentene (424 mg, 1.17 mmol)in anhydrous tetrahydrofuran (12 ml) at −78° C. under nitrogen. Theresulting solution was stirred for 15 minutes and triisopropyl borate(440 mg, 2.34 mmol) was added. The mixture was allowed to warm to roomtemperature, 1M hydrochloric acid (20 ml) was added and stirredvigorously for 15 minutes. After diluting with ether the organic phasewas dried (magnesium sulphate), evaporated and purified bychromatography on silica (1:4 ethyl acetate/iso-hexane) to give thetitle compound as a white solid (214 mg, 58%).

LC/MS: Rt 3.4, [2 MH−] 637.3.

General Procedure C(iii)

2-{2-[5-Chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4-carboxylicAcid Ethyl Ester

A mixture of 2-chloropyrimidine-4-carboxylic acid methyl ester (114 mg,0.66 mmol), 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid(209 mg, 0.66 mmol), potassium carbonate (729 mg, 5.28 mmol) andtetrakis(triphenylphosphine)palladium(0) (76 mg, 0.066 mmol) was stirredand heated in 1:1 toluene/ethanol (6 ml) at 90° C. under nitrogen for 2hours. After cooling the mixture was diluted with diethyl ether/waterand the organic phase dried (magnesium sulphate), evaporated to drynessand the residue purified by chromatography on silica (12% ethyl acetatein iso-hexane) to yield the title compound as a colourless gum (109 mg,38%).

LC/MS: Rt 3.8 [MH+] 435.3, 437.3.General Procedure D

5-[2-(2-Benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-3-aminobenzoic AcidMethyl Ester

A mixture of 3-amino-5-methoxycarbonylphenylboronic acid (161 mg, 0.82mmol), Pd(0) [PPh₃]₄ (50 mg, 5 mol %), potassium carbonate (905 mg, 6.6mmol) and 2-(2-benzyloxy-5-chloro)phenyl-1-bromocyclopent-1-ene (298 mg,0.82 mmol) in toluene-ethanol (1:1 10 mL) were stirred at 90° C., undernitrogen, for 2 hrs. After cooling the reaction mixture was poured ontowater (10 ml) and extracted with diethyl ether (2×10 ml). The combinedextracts were dried and evaporated. Flash chromatography[EtOAc/Iso-hexane 5:95-1:4] gave the product as a yellow oil 200 mg 56%

LC/MS: Rt=4.00 [M+H] 434 (1 Cl)General Procedure 4

3-[2-5-Bromo-2-hydroxyphenyl)cyclopent-1-enyl]-benzoic Acid

3-[2-(5-Bromo-2-methoxyphenyl)cyclopent-1-enyl]benzoic acid ethyl ester(416 mg, 10.0 mmol) in dichloromethane (5 mL) was cooled under nitrogento ˜40° C. and was treated with a molar solution of borontribromide indichloromethane (20 mL, 20.0 mmol). The reaction mixture was thenallowed to reach room temperature and kept stirring over night. Thereaction mixture was then quenched with ice/water (50/50 mL) and moredichloromethane (30 mL) was added. After stirring vigorously for 1.5 hr,the organic layer was separated, dried (magnesium sulphate), evaporateddown and chromatographed with 1% methanol in dichloromethane to give thetitle compound. (300 mg, 80%).

¹H NMR (400 MHz, CDCl₃) 2.08-2.19 (2H, m), 2.82-2.90 (2H, m), 3.00-3.08(2H, m), 6.72 (1H, d, J=4 Hz), 7.24-7.40 (4H, m), 7.94 (1H, d, J=4 Hz),7.99 (1H, s).

LC/MS [MH−] 359 Rt=3.74 min.General Procedure 5

6-{2-[5-Chloro-2-(4-chlorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid 4-chlorobenzyl Ester

6-[2-(5-Chloro-2-hydroxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylicacid (97 mg, 0.30 mmol) was refluxed in 2-butanone (4 mL) with4-chlorobenzyl bromide (140 mg, 0.70 mmol) and potassium carbonate (1.0g) under nitrogen for five hours. The reaction mixture was then filteredthrough highflo, evaporated down to an oil and chromatographed on aWater's sep-pak (10 g) with ether/isohexane (15/85) to give the titlecompound. (160 mg, 92%).

LC/MS [MH+] 556 Rt=5.5 min.General Procedure E

5-[2-(2-Benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-propionylaminobenzoicAcid Methyl Ester

A mixture of5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acidmethyl ester (55 mg, 0.12 mmol), propionyl chloride (13 mg, 0.14 mmol),and triethylamine (15 mg, 0.14 mmol) in dichloromethane (2 ml) wasstirred at room temperature for 30 minutes. The reaction mixture wasdiluted with EtOAc (10 ml) and washed with 5% NaHCO₃ (10 ml), 2M HCl (10ml), water (10 ml) and brine (10 ml). The organic phase was dried andevaporated to give the product as a colourless glass 50 mg 85%.

LC/MS: Rt=4.09[M+H] 490 (1 Cl).General Procedure F

F(i)6-[2-(5-Methyl-2-acetoxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylicAcid Ethyl Ester

6-{2-[5-Methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-pyridine-2-carboxylicacid ethyl ester (351 mg, 0.85 mmol) was dissolved in 48% hydrogenbromide in acetic acid (5 ml) and left at room temperature for 2 hours.The resulting mixture was poured into water/diethyl ether and basifiedwith potassium carbonate. The organic phase was separated, dried(magnesium sulphate) and chromatographed on silica to give the titlecompound as a colourless gum (310 mg, 100%).

LC/MS: Rt 3.4 [MH+] 366.4

F(ii)6-[2-(5-Methyl-2-hydroxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylicAcid Ethyl Ester

60% Sodium hydride (2 mg) was added to a solution of6-[2-(5-methyl-2-acetoxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylicacid ethyl ester in ethanol (5 ml) and left overnight at roomtemperature then diluted with water/diethyl ether and acidified withacetic acid. The organic phase was washed with saturated sodiumbicarbonate solution, dried (magnesium sulphate) and evaporated to givethe title compound as a pale yellow gum (271 mg, 99%).

LC/MS: Rt 3.3 [MH+] 324.4

F(iii)6-{2-[5-Methyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Ethyl Ester

A mixture of6-[2-(5-methyl-2-hydroxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylicacid ethyl ester (129 mg, 0.4 mmol), 4-fluorobenzyl bromide (83 mg, 0.44mmol) and potassium carbonate (138 mg, 1 mmol) in acetone (4 ml) wasstirred and refluxed for 20 hours. After cooling the mixture was dilutedwith water/diethyl ether and the organic phase dried (magnesiumsulphate) evaporated and purified by chromatography on silica (8% ethylacetate in iso-hexane) to give the title compound as a colourless gum(148 mg, 86%).

¹H NMR (CDCl₃)δ: 1.41 (3H, t, J=7 Hz), 2.04-2.09 (2H, m), 2.18 (3H, s),2.88-2.91 (2H, m), 3.11-3.15 (2H,m), 4.41 (2H, q, J=7 Hz), 4.91 (2H, s),6.80 (1H, d, J=8 Hz), 6.87 (1H, d, J=2 Hz), 6.95-7.04 (4H, m), 7.17-7.21(2H, m), 7.40 (1H, t, J=8 Hz), 7.79 (1H, d, J=8 Hz).General Procedure G

5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminoBenzoic Acid Ethyl Ester

5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl)-3-aminobenzoicacid ethyl ester (60 mg, 0.12 mmol), pyridine (11 μL, 0.137 mmol),methane sulphonyl chloride (11 μL, 0.137 mmol), and a catalytic amountof DMAP in 2 mL of dichloromethane were stirred at room temperature for2 hrs. The reaction mixture was poured into water and extracted withethyl acetate (3×10 mL). The combined organic layers were dried (MgSO₄),filtered and concentrated. Purification was carried out on a SPE usingiso-hexane containing a gradient of ethyl acetate (5-30%) to give therequired product as yellow oil (55 mg, 78%).

¹H NMR (CDCl3): 1.32 (3H,t,J=7.1), 2.06-2.13 (2H,m), 2.60 (3H,s), 2.88(2H,t,J=7.4), 2.92-296 (2H,m), 4.31 (2H,q,J=7.1), 5.11 (2H,s), 6.42(1H,s), 7.04 (1H,d,J=8.6), 7.11 (1H,s), 7.23-7.30 (5H,m), 7.33 (1H,d),7.54 (1H,s), 7.66 (1H,s).

LC/MS[MH−]=558 Rt=4.11.

General Procedure H

5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-morpholin-4-yl-benzoicAcid Ethyl Ester

5-{2-[5-trifluoromethyl-2-benzyloxyphenyl]cyclopent-1-enyl}-3-aminobenzoicacid ethyl ester (198 mg, 0.41 mmol), bis(2-bromoethyl)ether (0.15 mL,1.2 mmol), potassium carbonate (568 mg, 4.1 mmol) in 2.5 mL of2-butanone were refluxed for 24 hrs. Upon cooling, the reaction mixturewas poured into water and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried (MgSO₄), filtered and concentrated.Purification was carried out on a SPE using iso-hexane containing agradient of ethyl acetate (5-20%) to give the required product as yellowoil.

¹H NMR (CDCl₃): 1.31 (3H,t,J=7.1), 2.07-2.11 (2H,m), 2.79 (4H,t,J=4.8),2.87 (2H,t,J=7.3), 2.95 (2H,t,J=7.5), 3.69 (4H,t,J=4.8), 4.28(2H,q,J=7.1), 5.29 (2H,s), 6.72 (1H,s), 6.93 (1H,d,J=8.6), 7.16-7.42(9H,m).

LC/MS[MH+]=552, 553 Rt=4.37.

General Procedure J

5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(4-chloro-butanoylamino)-benzoicAcid Ethyl Ester

4-chlorobutyryl chloride (0.026 mL, 0.22 mmol), was added dropwise to asolution of5-{2-[5-tryfluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoicacid ethyl ester (100 mg, 0.21 mmol) and triethylamine (0.032 mL, 0.22mmol) in DCM (4 mL). The resulting mixture was stirred for 2 hrs at roomtemperature, then was poured into a saturated solution of (NaHCO₃ 10 mL)and extracted with ethyl acetate (20 mL). The organic phase was thenwashed sequentially with 2M HCl, H₂O and brine. The organic layer wasthen dried over MgSO₄ and evaporated to give a yellow oil that was usedwith no further purification.

¹H NMR (CDCl₃): 1.24 (3H,t,J=7.1), 2.01-2.18 (4H,m), 2.50 (2H,t,J=6.7),2.87 (4H,m), 3.62 (2H,t,J=6.0), 4.23 (2H,q,J=7.1), 5.04 (2H,s), 6.95(1H,d,J=8.6), 7.05-7.54 (9H, m), 7.84 (1H, s).

General Procedure K

5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-pyrrolidin-1-yl)-benzoicAcid Ethyl Ester

5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(4-chloro-butanoylamino)-benzoicacid ethyl ester (140 mg, 0.24 mmol) and NaH (10.5 mg, 0.26 mmol, 60%dispersion in oil) in THF (3 mL), were stirred at room temperature for 4hrs. The reaction mixture was poured into water and extracted with ethylacetate (10×3 mL), the combined organic layers were dried over MgSO₄ andconcentrated. Purification was carried out on a Biotage® using 40% ofethyl acetate in iso-hexane to give the required product as an orangeoil (60 mg, 46%).

¹H NMR (CDCl₃): 1.26 (3H,t,J=7.1), 2.01-2.18 (4H,m), 2.52 (2H,t,J=6.7),2.88 (2H,t,J=7.6), 2.97 (2H,t,J=7.4), 3.44 (2H,t,J=7.0), 4.26(2H,q,J=7.2), 5.06 (2H,s), 6.96 (1H,d,J=8.6), 7.18-7.58 (9H, m), 8.09(1H, s).Standard Hydrolysis Procedure

The ester (0.5 mmol) was dissolved in methanol or ethanol (2 ml) and 2Msodium hydroxide (1 ml) added. The mixture was stirred at from roomtemperature to reflux for from 30 minutes to 20 hours until the reactionwas complete by tlc. The solution was diluted with water then extractedwith isohexane or diethyl ether and acidified to pH4 with eitherhydrochloric acid or acetic acid. The mixture was extracted with diethylether or dichloromethane. The organic solution was dried over magnesiumsulphate and evaporated to give the title compound.

4-[(4-Fluorobenzyl)oxy]benzotrifluoride

Prepared by general procedure A(i) but using 4-fluorobenzyl bromideinstead of benzyl bromide.

¹H NMR (CDCl₃): δ: 5.07 (2H, s), 7.02 (2H, d, J=9 Hz), 7.07-7.11 (2H,m), 7.39-7.42 (2H, m), 7.52 (2H, d, J=9 Hz)

2-[(4Fluorobenzyl)oxy]-5-trifluoromethyliodobonzene

Prepared by general procedure A(ii) but using4-[(4-fluorobenzyl)oxy]benzotrifluoride instead of4-(benzyloxy)benzotrifluoride.

¹H NMR (CDCl₃): δ: 5.16 (2H, s), 6.88 (1H, d, J=9 Hz), 7.08-7.13 (2H,m), 7.44-7.48 (2H, m), 7.54-7.57 (1H, dd, J=2 Hz, J=9 Hz), 8.04 (1H, d,J=2 Hz).

2-[(4-Fluorobenzyl)oxy]-5-trifluoromethylbenzeneboronic Acid

Prepared by general procedure A(iii) but using4-[(4-fluorobenzyl)oxy]-3-iodobenzotrifluoride instead of4-benzyloxy-3-iodobenzotrifluoride.

¹H NMR (d₆DMSO) δ: 5.22 (2H, s), 7.20-7.26 (3H, m), 7.54-7.58 (2H, m),7.71 (1H, d, J=9 Hz), 7.75 (1H, s), 8.03 (2H, s).

4-[(2,4-Difluorobenzyl)oxy]benzotrifluoride

Prepared by general procedure A(i) but using 2,4-difluorobenzyl bromideinstead of benzyl bromide.

¹H NMR (CDCl₃): δ: 5.12 (2H, s), 6.89 (2H, dt, J=2 Hz, J=9 Hz),7.02-7.05 (2H, d, J=9 Hz), 7.33-7.49 (1H, q, J=8 Hz, J=15 Hz), 7.56 (2H,d, J=9 Hz)

2-[(2,4-Difluorobenzyl)oxy]-5-trifluoromethyliodobenzene

Prepared by general procedure A(ii) but using4[(2,4-difluorobenzyl)oxy]benzotrifluoride instead of4-(benzyloxy)benzotrifluoride.

¹H NMR (CDCl₃): δ: 5.21 (2H, s), 6.84-6.95 (3H, m), 7.55-7.65 (2H, m),8.04 (1H, s)

2-[(2,4-Difluorobenzyl)oxy]-5-trifluoromethylbenzeneboronic Acid

Prepared by general procedure A(iii) but using4-[(2,4-difluorobenzyl)oxy]-3-iodobenzotrifluoride instead of4-benzyloxy-3-iodobenzotrifluoride.

¹H NMR (d₆DMSO) δ: 5.26 (2H, s), 7.16 (1H, dt, J=2 Hz, J=9 Hz) 7.27 (1H,d, J=9 Hz), 7.33 (1H, dt, J=2 Hz, J=9 Hz), 7.68-7.75 (3H, m), 8.01 (2H,s).

2-Benzyloxy-5-bromoiodobenzene.

Prepared as general procedure A(i) from 2-iodo-4-bromophenol

¹H NMR (CDCl₃): 5.10 (2H, s), 6.69 (1H, d, J=9 Hz), 7.23-7.46 (6H, m),7.88 (1H,s).

2-Benzyloxy-5-bromobenzeneboronic Acid

Prepared as general procedure A(iii) from2-benzyloxy-5-bromoiodobenzene.

¹H NMR (CDCl₃): 5.12 (2H,s), 5.78 (2H,s), 6.58 (1H,d,J=9 Hz), 7.34-7.39(5H, m), 7.40 (1H,d,J=9 Hz), 7.95 (1H,s).

LC/MS: Rt=3.44 [M−H] 305, 307 (1Br)

2-(4-Fluorobenzyl)oxy-5-bromoiodobenzene

Prepared as general procedure A(i) from 2-iodo-4-bromophenol.

¹H NMR (CDCl₃): 5.06 (2H, s), 6.69 (1H, d, J=9 Hz), 7.07-7.10 (2H, m),7.35-7.45 (3H, m), 7.89 (1H, s).

2-(4-Fluorobenzyl)oxy-5-bromobenzeneboronic Acid

Prepared as general procedure A(iii) from2-(4-fluorobenzyl)oxy-5-bromoiodobenzene.

¹H NMR (CDCl₃): 5.07 (2H, s), 5.83 (2H, s), 6.84 (1H, d, J=9 Hz), 7.10(2H, m), 7.37 (2H, m), 7.50 (1H, d, J=9 Hz), 7.95 (1H, s).

2-(2,4-Difluorobenzyl)oxy-5-bromoiodobenzene

Prepared as general procedure A(i) from 2-iodo-4-bromophenol.

¹H NMR (CDCl₃): 5.12 (2H, s), 6.74-6.95 (3H, m), 7.40 (1H, d, J=9 Hz),7.57-7.63 (1H, m), 7.90 (1H, s).

2-(2,4-Difluorobenzyl)oxy-bromobenzeneboronic Acid

Prepared as general procedure A(iii) from2-(2,4-difluorobenzyl)oxy-5-bromoiodobenzene.

¹H NMR (CDCl₃): 5.14 (2H, s), 5.77 (2H, br s), 6.86-6.95 (3H, m),7.36-7.42 (1H, m), 7.52 (1H, d, J=9 Hz), 7.95 (1H, s).

2-[(4-Fluorobenzyl)oxy]-5-chloroiodobenzene

Prepared as general procedure A(i) from 2-iodo-5-chlorophenol.

¹HNMR (CDCl₃): 5.08 (2H, s), 6.75 (1H, d, J=8 Hz), 7.06 (1H, d, J=8 Hz),7.07 (1H, d, J=8 Hz), 7.23 (1H, s), 7.43-7.46 (2H, m), 7.76 (1H, s).

2-[(4-Fluorobenzyl)oxy]-5-chlorobenzeneboronic Acid

Prepared as general procedure A(iii) from2-[(4-fluorobenzyl)oxy]5-chloroiodobenzene

¹H NMR (CDCl₃): 5.07 (2H, s), 6.89 (1H, d, J=8 Hz), 7.09 (2H, m),7.35-7.40 (3H, m), 7.81 (1H, s).

1-Bromo-2-[2-(4-fluorobenzyloxy)-5-trifluoromethylphenyl)cyclopentene

Prepared by general procedure C(i) but using2-(4-fluorbenzyloxy)-5-trifluoromethylphenylboronic acid instead of2-benzyloxy-5-chlorophenylboronic acid.

LC/MS: Rt 4.26 [MH−] 414.9

2-(2-Benzyloxy-5-trifluoromethylphenyl)cyclopentene-1-boronic Acid

Prepared as a colourless gum by general procedure C(ii) but using1-bromo-2-(2-benzyloxy-5-trifluoromethylphenyl)cyclopentene instead of1-bromo-2-(2-benzyloxy-5-chlorophenyl)cyclopentene.

LC/MS: Rt 3.66 [2M-H₂O—] 705.1

1-Bromo-2-[2-4-fluorobenzyloxy)-5-chlorophenyl]cyclopentene

Prepared by general procedure C(i) but using2-(4-fluorobenzyloxy)-5-chlorophenylboronic acid instead of2-benzyloxy-5-chlorophenylboronic acid.

¹H NMR (CDCl₃) δ: 1.99-2.06 (2H, m), 2.64-2.69 (2H, m), 2.76-2.81 (2H,m), 5.01 (2H, s), 6.83 (1H, d, J=9 Hz), 7.04-7.09 (2H, m), 7.17-7.36(4H, m).

2-[2-(4-Fluorobenzyloxy)-5-chlorophenyl]cyclopentene-1-boronic Acid

Was prepared as a colourless gum by general procedure C(ii) but using1-bromo-2-[2-(4-fluorobenzyloxy)-5-chlorophenyl]cyclopentene instead of1-bromo-2-(2-benzyloxy-5-chlorophenyl)cyclopentene.

LC/MS: Rt 3.42 [2M-H₂O—] 675.3

3-(2-Bromocyclopent-1-enyl)-6-aminobenzoic Acid Ethyl Ester

Prepared by general procedure B(ii) but using 2-amino-5-iodobenzoic acidethyl ester instead of 5-iodo-2-methylbenzoic acid ethyl ester.

¹H NMR (CDCl₃)δ: 1.39 (3H, t, J=7 Hz), 1.98-2.06 (2H, m), 2.71-2.76 (2H,m), 2.81-2.86 (2H, m) 4.33 (2H, q, J=7 Hz), 5.80 (2H, br s), 6.65 (1H,d, J=9 Hz), 7.65 (1H, dd, J=9 Hz, 2 Hz), 8.14 (1H, d, J=2 Hz).

1-Bromo-2-(2-benzyloxy-5-methylphenyl)cyclopentene

Was prepared as a white solid by general procedure C(i) but using2-benzyloxy-5-methylphenylboronic acid instead of2-benzyloxy-5-chlorophenylboronic add.

¹H NMR (CDCl₃)δ: 2.01-2.07 (2H, m), 2.30 (3H, s), 2.69-2.74 (2H, m),2.76-2.80 (2H, m), 5.05 (2H, s), 6.83 (1H, d, J=9 Hz), 7.02-7.08 (2H,m), 7.30-7.40 (5H, m).

2-(2-Benzyloxy-5-methylphenyl)cyclopentene-1-boronic Acid

Was prepared in 46% yield as a white solid by general procedure C(ii)but using 1-bromo-2-(2-benzyloxy-5-methylphenyl)cyclopentene instead of1-bromo-2-(2-benzyloxy-5-chlorophenyl)cyclopentene.

¹H NMR (CDCl₃)δ: 1.90-1.97 (2H, m), 2.27 (3H, s), 2.63-2.68 (2H, m),2.72-2.76 (2H, m), 4.49 (2H, s), 5.05 (2H, s), 6.88 (1H, d, J=8 Hz),6.98 (1H, d, J=2 Hz), 7.04 (1H, dd, J=8 Hz, 2 Hz), 7.26-7.36 (5H, m).

6-{2-[5-Methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-pyridine-2-carboxylicAcid Ethyl Ester

Prepared in 80% yield as a colourless gum by general procedure C(iii)but using 2-(2-benzyloxy-5-methylphenyl)cyclopentene-1-boronic acidinstead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid and6-bromopicolinic acid methyl ester instead of2-chloropyrimidine-4-carboxylic acid methyl ester.

LC/MS: Rt 3.9 [MH+] 414.4.

5-{2-[5-trifluoromethyl-2-benzyloxyphenyl]cyclopenten-1-enyl}-3-aminobenzoicAcid Ethyl Ester

Prepared by general procedure B(iii) using(5-trifluoromethylphenyl-2-(benzyloxy)boronic acid and3-amino-5-(2-bromocyclopent-1-enyl}-benzoic acid methyl ester.

¹HNMR (CDCl3): 1.25 (3H,t), 2.04-2.08 (2H,m), 2.84-292 (4H,m), 3.53(2H,br s), 4.21 (2H, q), 5.02 (2H, s), 6.54 (1H, s), 6.93 (1H,d, J=8.6),7.12-7.29 (8H,m), 7.32 (1H, d, J=8.5).

LC/MS[MH+]=482 Rt=4.12

6-{2-[5-Methyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Ethyl Ester

Prepared by general method F(iii) but using 2,4-difluorobenzyl bromideinstead of 4-fluorobenzyl bromide.

LC/MS: Rt 3.9 [MH+] 450.4.

2-[2-(4-Fluorobenzyloxy)-5-trifluoromethylphenyl]cyclopentene-1-boronicAcid

Prepared in 40% yield as a colourless gum by general method C(ii) butusing1-bromo-2-[2-(4-fluorobenzyloxy)-5-trifluoromethylphenyl]cyclopenteneinstead of 1-bromo-2-(2-benzyloxy-5-chlorophenyl)cyclopentene.

LC/MS: Rt 3.66, [2MH-H₂O—] 741.0

2-{5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-pyridine-4-carboxylicAcid Ethyl Ester

Prepared by general procedure C(iii) but using2-[2-(4-fluorobenzyloxy)-5-trifluoromethylphenyl]cyclopentene-1-boronicacid instead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronicacid and 2-bromoisonicotinic acid ethyl ester instead of2-chloropyrimidine-4-carboxylic acid methyl ester.

LC/MS: Rt 4.19, [MH+] 486.1.

4-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Ethyl Ester

Prepared by general procedure C(iii) but using2-[2-(4-fluorobenzyloxy)-5-trifluoromethylphenyl]cyclopentene-1-boronicacid instead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronicacid and 4-iodoipicolinic acid methyl ester instead of2-chloropyrimidine-4-carboxylic acid methyl ester.

LC/MS: Rt 4.02, [MH+] 486.1

2-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-pyridine-4-carboxylicAcid Ethyl Ester

Prepared by general procedure C(iii) but using2-[2-benzyloxy)-5-trifluoromethylphenyl]cyclopentene-1-boronic acidinstead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid and2-bromoisonicotinic acid ethyl ester instead of2-chloropyrimidine-4-carboxylic acid methyl ester.

LC/MS: Rt 4.19, [MH+] 468.1

4-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-pyridine-2-carboxylicAcid Ethyl Ester

Prepared by general procedure C(iii) but using2-[2-(benzyloxy)-5-trifluoromethylphenyl]cyclopentene-1-boronic acidinstead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid and4-iodoipicolinic acid methyl ester instead of2-chloropyrimidine-4-carboxylic acid methyl ester.

¹H NMR (CDCl₃)δ: 1.35 (3H, t, J=7 Hz), 2.10-2.15 (2H, m), 2.89-2.97 (4H,m), 4.38 (2H, q, J=7 Hz) 4.99 (2H, s), 6.98-7.03 (2H, m), 7.15-7.17 (2H,m), 7.26-7.33 (5H, m), 7.51 (1H, dd, J=7 Hz, 2 Hz), 7.78 (1H, d, J=1Hz), 8.45 (1H, d, J=5 Hz).

6-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-aminopyrazine-2-carboxylicAcid Ethyl Ester

Prepared by general procedure C(iii) but using2-[2-(benzyloxy)-5-trifluoromethylphenyl]cyclopentene-1-boronic acidinstead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid and3-amino-6-bromopyrazine-2-carboxylic acid methyl ester instead of2-chloropyrimidine 4-carboxylic acid methyl ester.

LC/MS: Rt 4.08, [MH+] 484.1

2-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4-carboxylicAcid Ethyl Ester

Prepared by general procedure C(iii) but using2-[2-(4-fluorobenzyloxy)-5-trifluoromethylphenyl]cyclopentene-1-boronicacid instead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronicacid.

LC/MS: Rt 3.8, [MH+] 487.3

2-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4-carboxylicAcid Ethyl Ester

Was prepared by general procedure C(iii) but using2-[2-(4-fluorobenzyloxy)-5-chlorophenyl]cyclopentene-1-boronic acidinstead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid.

LC/MS: Rt 3.8, [MH+] 453.3, 455.3

6-{2-[5-Methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicAcid Ethyl Ester

Prepared by general procedure C(iii) but using2-[2-(benzyloxy)-5-methylphenyl]cyclopentene-1-boronic acid instead of2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid and6-chloropyrazine-2-carboxylic acid ethyl ester instead of2-chloropyrimidine-4-carboxylic acid methyl ester.

LC/MS: Rt 3.8, [MH+] 415.5

3-{2-[5-Methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoic AcidEthyl Ester

Prepared by general procedure C(iii) but using2-(2-benzyloxy-5-methylphenyl)cyclopentene-1-boronic acid instead of2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid and2-amino-5-iodobenzoic acid ethyl ester instead of2-chloropyrimidine-4-carboxylic acid methyl ester.

LC/MS: Rt 4.0 [MH+] 428.5

6-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-pyridine-2-carboxylicAcid Methyl Ester

Prepared by general procedure 3 but using6-(2-bromocyclopent-1enyl)pyridine-2-carboxylic acid methyl esterinstead of 3-(2-bromocyclopent-1-enyl)benzoic acid ethyl ester and2-benzyloxy-5-trifluoromethylphenylboronic acid instead of5-chloro-2-methoxyphenylboronic acid.

LC/MS: Rt 4.04 [MH+] 454.1

6-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Methyl Ester

Prepared by general procedure 3 but using6-(2-bromocyclopent-1-enyl)-pyridine-2-carboxylic acid methyl esterinstead of 3-(2-bromocyclopent-1-enyl}-benzoic acid ethyl ester and2-(4-fluorobenzyloxy)-5-trifluoromethylphenylboronic acid instead of5-chloro-2-methoxyphenylboronic acid.

LC/MS: Rt 4.04 [MH+] 472.1

6-{2-[5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-pyridine-2-carboxylicAcid Methyl Ester

Prepared by general procedure 3 but using6-(2-bromocyclopent-1-enyl}-pyridine-2-carboxylic acid methyl esterinstead of 3-(2-bromocyclopent-1-enyl)benzoic acid ethyl ester and2-(2,4-difluorobenzyloxy)-5-trifluoromethylphenylboronic acid instead of5-chloro-2-methoxyphenylboronic acid.

LC/MS: Rt 4.08 [MH+] 490.1

3-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl})-aminobenzoicAcid Ethyl Ester

Prepared by general procedure C(iii) but using2-benzyloxy-5-trifluoromethylphenylboronic acid instead of2-benzyloxy-5-chlorophenylboronic acid and(3-(2-bromocyclopent-1-enyl)-6-aminobenzoic acid ethyl ester instead of3-(2-bromo-cyclopent-1-enyl)-methylbenzoic acid ethyl ester.

LC/MS: Rt 4.32 [MH+] 482.0.

3-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoicAcid Ethyl Ester

Prepared by general procedure C(iii) but using2-(4-fluorobenzyloxy)-5-trifluoromethylphenylboronic acid instead of2-(benzyloxy)-5-chlorophenylboronic add and3-(2-bromocyclopent-1-enyl)-6-aminobenzoic acid ethyl ester instead of3-(2-bromo-cyclopent-1-enyl)-6-methylbenzoic acid ethyl ester.

LC/MS: Rt 4.32 [MH+] 500.0.

3-{2-[5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl)-6-aminobenzoicAcid Ethyl Ester

Prepared by general procedure C(iii) but using2-(2,4-difluorobenzyloxy)-5-trifluoromethylphenylboronic acid instead of2-(benzyloxy)-5-chlorophenylboronic acid and3-(2-bromocyclopent-1-enyl}-6-aminobenzoic acid ethyl ester instead of3-(2-bromo-cyclopent-1-enyl)-methylbenzoic acid ethyl ester.

LC/MS: Rt 4.35 [MH+] 518.0.

3-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-acetamidobenzoicAcid Ethyl Ester

Prepared by general procedure E but using acetyl chloride instead ofpropionyl chloride and3-{2[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoicacid ethyl ester instead of5-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-2-aminobenzoic acidmethyl ester.

LC/MS: Rt 4.0 [MH+] 524.4

3-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-acetamidobenzoicAcid Ethyl Ester

Prepared by general procedure E but using acetyl chloride instead ofpropionyl chloride and(3-{2[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoicacid ethyl ester instead of5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acidmethyl ester.

LC/MS: Rt 4.0 [MH+] 542.4.

3-{2-[5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-6acetamidobenzoic Acid Ethyl Ester

Prepared by general procedure E but using acetyl chloride instead ofpropionyl chloride and(3-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoicacid ethyl ester instead of5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acidmethyl ester.

LC/MS: Rt 4.0 [MH+] 560.4

3-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicAcid Ethyl Ester

Prepared by general procedure E but using3-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-aminobenzoicacid ethyl ester instead of5-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-2-aminobenzoic acidmethyl ester.

LC/MS: Rt 4.15 [MH−] 536.1

3-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicAcid Ethyl Ester

Prepared by general procedure E but using3-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-aminobenzoicacid ethyl ester instead of5-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-2-aminobenzoic acidmethyl ester.

LC/MS: Rt 4.16 [MH−] 554.2

3-{2-[5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicAcid Methyl Ester

Prepared by general procedure E but using3-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-aminobenzoicacid methyl ester instead of5-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-2-aminobenzoic acidmethyl ester.

LC/MS: Rt 4.07 [MH−] 558.2

5-[2-(2-Benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-2-aminobenzoic AcidMethyl Ester

Prepared by general procedure C(iii) but using 2-amino-5-bromobenzoicacid methyl ester instead of 2-chloropyrimidine-carboxylic acid methylester.

LC/MS: Rt 3.8 [MH+] 434.3, 436.3.

3-{2-[5-Bromo-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-aminobenzoic AcidMethyl Ester

Prepared by general procedure 3 but using3-amino-5-2-bromocyclopent-1-enyl)benzoic acid methyl ester instead of3-(2-bromocyclopent-1-enyl}-benzoic acid ethyl ester and2-(benzyloxy)-5-bromophenylboronic acid instead of5-chloro-2-methoxyphenylboronic acid.

LC/MS: Rt 4.03 [MH+] 478.0, 480.0.

3-{2-[5-Bromo-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-aminobenzoicAcid Methyl Ester

Prepared by general procedure 3 but using3-amino-5-(2-bromocyclopent-1-enyl)benzoic acid methyl ester instead of3-(2-bromocyclopent-1-enyl}-benzoic acid ethyl ester and2-(4-fluorobenzyloxy-5-bromophenylboronic acid instead of5-chloro-2-methoxyphenylboronic acid.

LC/MS: Rt 4.04 [MH+] 496.0, 498.0

3-{2-[5-Bromo-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-aminobenzoicAcid Methyl Ester

Prepared by general procedure 3 but using3-amino-5-(2-bromocyclopent-1-enyl)benzoic acid methyl ester instead of3-(2-bromocyclopent-1-enyl)benzoic acid ethyl ester and2-(2,4-difluorobenzyloxy)-5-bromophenylboronic acid instead of5-chloro-2-methoxyphenylboronic acid.

LC/MS: Rt 4.07 [MH+] 514.0, 516.0.

3-{2-[5-Bromo-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicAcid Methyl Ester

Prepared by general procedure E but using3-{2-[5-bromo-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-aminobenzoic acidmethyl ester instead of5-[-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acidmethyl ester.

LC/MS: Rt 4.08 [MH+] 534.1, 536.1

3-{2-[5-Bromo-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicAcid Methyl Ester

Prepared by general procedure E but using3-{2-[5-bromo-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-aminobenzoicacid methyl ester instead of5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acidmethyl ester.

LC/MS: Rt 4.09 [MH+] 552.0, 554.0

3-{2-[5-Bromo-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicAcid Methyl Ester

Prepared by general procedure E but using3-{2-[5-bromo-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-aminobenzoicacid methyl ester instead of5-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-2-aminobenzoic acidmethyl ester.

LC/MS: Rt 4.12 [MH+] 570.1, 572.1.

3-{2-[5-Methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-acetamidobenzoicAcid Ethyl Ester

Prepared by general procedure E but using acetyl chloride instead ofpropionyl chloride and3-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoic acidethyl ester instead of5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acidmethyl ester.

LC/MS: Rt 4.0 [MH+] 470.4.

4-Fluoro-2-(2-bromocyclopent-1-enyl)anisole

Prepared using general procedure C(i) but using2-methoxy-5-fluorophenylboronic acid instead of2-benzyloxy-5-chlorophenylboronic acid.

¹H NMR (CDCl₃): δ: 2.02-2.10 (2H, m), 2.67-2.72 (2H, m), 2.78-2.82 (2H,m), 3.79 (3H, s), 6.80-6.83 (1H, dd, J=5 Hz, J=9 Hz), 6.93-7.00 (2H, m).

5-[2-(5-fluoro-2-methoxyphenyl)cyclopent-1-enyl]-3-aminobenzoic AcidMethyl Ester

4-Fluoro-2-(2-bromocyclopent-1-enyl)anisole (271 mg, 1 mmol),(3-amino-5-methoxycarbonyl)phenylboronic acid (195 mg, 1 mmol) andpotassium carbonate (1.1 g, 8 mmol) were stirred under nitrogen in 1:1toluene: ethanol (4 ml) and tetrakis(triphenylphosphine)palladium(0)(116 mg, 0.1 mmol) added. The resulting mixture was heated at 80° C. ina Smithcreator® microwave for 20 minutes. After cooling, diethyl ether(10 ml) and water (10 ml) were added. The organic layer was washed withwater, dried (MgSO₄) and evaporated. The product was purified by flashchromatography (silica gel, 10-30% ethyl acetate: isohexane) to give thetitle compound as a pale orange solid (143 mg, 42%).

LC/MS [MH+]=342, RT=3.57 min.

5-[2-(5-fluoro-2-methoxyphenyl)cyclopent-1-enyl]-3-propionamido)benzoicAcid Methyl Ester

Prepared by general method E but using5-[2-(5-fluoro-2-methoxyphenyl)cyclopent-1-enyl]-3-aminobenzoic acidmethyl instead of5-2[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acidmethyl ester.

LC/MS [MH+]=398, RT=3.41 min.

5-[2-(5-fluoro-2-hydroxyphenyl)cyclopent-1-enyl]-4(propionamido)benzoicAcid

Prepared by general procedure 4 but using5[2-(5-fluoro-2-methoxyphenyl)cyclopent-1-enyl]-3-(propionamido)benzoicacid methyl ester instead of3-[2-(5-bromo-2-methoxyphenyl)cyclopent-1-enyl]benzoic acid ethyl ester.

LC/MS [MH+]=370, RT=3.12 min.

5-{2-[5-fluoro-2(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(propionamido)benzoicAcid 4-fluorobenzyl Ester

Prepared by general procedure 5 but using5-[2-(5-fluoro-2-hydroxyphenyl)cyclopent-1-enyl]-3-(propionamido)benzoicacid instead of6-[2-(5-chloro-2-hydroxyphenyl)cyclopent-1-enyl]pyridine-2 carboxylicacid, 4-fluorobenzyl bromide instead of 4-chlorobenzyl bromide andacetone instead of 2-butanone.

LC/MS [MH+J=586, RT=3.95 min.

4-Methyl-2-(2-bromocyclopent-1-enyl)anisole

Prepared using general procedure C(i) but using2-methoxy-5-methylphenylboronic acid instead of2-benzyloxy-5-chlorophenylboronic acid.

¹H NMR (CDCl₃) δ: 2.03-2.09 (2H, m), 2.30 (3H, s) 2.67-2.72 (2H, m),2.77-2.82 (2H, m), 3.79 (3H, s), 6.80 (1H, d, J=8 Hz), 7.07 (1H, d, J=8Hz), 7.26 (1H, s).

5[2-(5-methyl-2-methoxyphenyl)cyclopent-1-enyl]-3-aminobenzoic Acidmethyl Ester

Prepared using general procedure D but using4-methyl-2-(2-bromocyclopent-1-enyl)anisole instead of1-bromo-2-(2-benzyloxy-5-chlorophenyl)cyclopentene.

LC/MS [MH+]=338, RT=3.38 min.

5-[2-5-methyl-2-methoxyphenyl)cyclopent-1-enyl]-3-(propionamido)benzoicAcid Methyl Ester

Prepared by general method E but using5-[2-(2-methoxyphenyl-5-methyl)cyclopent-1-enyl]-3-aminobenzoic acidmethyl ester instead of 5-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-2-aminobenzoic acid methyl ester

LC/MS [MH+]=394, RT=3.47 min.

5-[2-(5-methyl-2-hydroxyphenyl)cyclopent-1-enyl]-3-(propionamido)benzoicAcid

Was prepared by general procedure 4 but using 5-[2-(2-methoxy-5methylphenyl)cyclopent-1-enyl]-3-(propionamido)benzoic acid methyl esterinstead of 3-[2-(5-bromo-2-methoxyphenyl)cyclopent-1-enyl]benzoic acidethyl ester.

LC/MS [MH+]=366, RT=3.27 min.

5-{2-[5-methyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl)-3-(propionamido)benzoicAcid 4-fluorobenzyl Ester

Prepared by general procedure 5 but using5-[2-(2-hydroxy-5-methylphenyl)cyclopent-1-enyl]-3-(propionamido)benzoicacid instead of6-[2-(5-chloro-2-hydroxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylicacid, 4-fluorobenzyl bromide instead of 4-chlorobenzyl bromide andacetone instead of 2-butanone.

LC/MS [MH+]=582, RT=4.30 min.

5-{2-[5-methyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(propionamido)benzoicAcid 2,4-difluorobenzyl Ester

Prepared by general procedure 5 but using5-[2-(2-hydroxy-5-methylphenyl)cyclopent-1-enyl]-3-(propionamido)benzoicacid instead of6-[2-(5-chloro-2-hydroxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylicacid, 2,4-difluorobenzyl bromide instead of 4-chlorobenzyl bromide andacetone instead of 2-butanone.

LC/MS [MH+]=618, RT=4.36 min.

2-(2-Bromocyclopent-1-enyl}isonicotinic Acid Ethyl Ester

Prepared according to general procedure B(ii) to give the product as ayellow oil 410 mg 28%

LC/MS: Rt=3.34 [M+H] 296, 298 (1 Br).

2-{2-[5-Chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}isonicotinicAcid Ethyl Ester

Prepared according to general procedure B(iii) to give the product as ayellow oil 76 mg 31%.

LC/MS: Rt=3.92 [M+H] 470 (1 Cl)

2-{2-[5-Chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}isonicotinicAcid Ethyl Ester

Prepared according to general procedure B(iii) to give the product as ayellow oil 53 mg 22%

LC/MS: Rt=3.90 [M+H] 452 (1 Cl)

2-{2-[5-Chloro-2-benzyloxyphenyl]cyclopent-1-enyl}isonicotinic AcidEthyl Ester

Prepared according to general procedure B(iii) to give the product as ayellow oil 67 mg 41%

LC/MS: Rt=3.88 [M+H] 434 (1 Cl)

2-{2-[5-Bromo-2-(benzyloxy)phenyl]cyclopent-1-enyl}isonicotinic AcidEthyl Ester

Prepared according to general procedure B(iii) to give the product as ayellow gum 45 mg 27%

LC/MS: Rt=3.92 [M+H] 496, 498 (1 Br).

5-[2-(2-Benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-3-aminobenzoic AcidMethyl Ester

Prepared according to general procedure B(iii) to give the product as ayellow oil 200 mg 56%

LC/MS: Rt=4.00 [M+H] 434 (1 Cl)

5-[2-(2-Benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-3-propionylaminobenzoicAcid Methyl Ester

Prepared by general procedure E but using5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-3-aminobenzoic acidmethyl ester instead of5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acidmethyl ester.

LC/MS: Rt=4.04 [M+H] 490 (1 Cl).

5-[2-(2-Benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-3-isobutyrylaminobenzoicAcid Methyl Ester

Prepared by general procedure E but using5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-3-aminobenzoic acidmethyl ester instead of5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acidmethyl ester and 2-methylpropionyl chloride instead of propionylchloride.

LC/MS: Rt=4.13 [M+H] 504 (1 Cl)

2-[5-trifluoromethyl-2-benzyloxyphenyl]-1-bromocyclopent-1-ene

Prepared by general procedure C(i) using2-benzyloxy-5-trifluoromethylphenylboronic acid instead of2-benzyloxy-5-chlorophenylboronic acid.

¹H NMR (CDCl₃) δ: 2.01-2.08 (2H, m), 2.70-2.74 (2H, m), 2.77-2.82 (2H,m), 5.14 (2H, s), 6.97 (1H, d, J=8.6 Hz), 7.31-7.39 (5H, m), 7.49 (1H,dd, J=8.64,Hz), 7.54 (1H, s).

5-{2-[5-trifluoromethyl-2-benzyloxyphenyl]cyclopent-1-enyl}-3-aminobenzoicAcid Ethyl Ester

Prepared by general procedure B(iii)

¹H NMR (CDCl₃) δ: 1.25 (3H, t, J=7.1 Hz), 2.04-2.08 (2H, m), 2.84-2.92(4H, m), 3.53 (2H, bs), 4.21 (2H, q, J=7.1 Hz), 5.02 (2H, s), 6.54 (1H,s), 6.93 (1H, d, J=8.6 Hz), 7.12-7.29 (8H, m), 7.32 (1H, d, J=8.5 Hz).

LC/MS[MH+]=482 Rt=4.12.

5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoicAcid Ethyl Ester

Prepared by general procedure B(iii)

¹H NMR (CDCl₃) δ: 1.25 (3H, t, J=7.1 Hz), 2.04-2.08 (2H, m), 2.82-2.91(4H, m) 3.55 (2H bs), 4.22 (2H, q, J=7.2 Hz), 4.94 (2H, s), 6.53 (1H,s), 6.91 (1H, d, J=8.6 Hz), 6.98 (2H, t, J=8.7 Hz), 7.12-7.16 (4H, m),7.36 (1H, s), 7.44 (1H, dd, J=8.6 Hz).

LC/MS[MH+]=500 Rt=3.9.

5-{2-[5-trifluoromethyl-2-(4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoicAcid Ethyl Ester

Prepared by general procedure B(iii)

¹H NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 1.99-2.08 (2H, m), 2.81 (2H,t, J=7.5 Hz), 2.90 (2H, t, J=7.5 Hz), 3.59 (2H, br s), 4.22 (2H, q,J=7.1 Hz), 5.0 (2H, s), 6.53 (1H, s), 6.79 (2H, t, J=8.4 Hz), 6.95 (1H,d, J=8.6 Hz), 7.06-7.14 (3H, m), 7.36 (1H, s,), 7.46 (1H, d, J=8.0 Hz).

LC/MS[MH+]=518 Rt=3.9.

5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoicAcid Methyl Ester/Ethyl Ester

Prepared by general procedure B(iii)

LC/MS[MH+]=452, 454 Rt=4.06 LC/MS[MH+]=466 Rt=4.15

5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoicAcid Methyl Ester/Ethyl Ester

Prepared by general procedure B(iii)

LC/MS[MH+]=470, 472 Rt=4.01 LC/MS[MH+]=484, 486 Rt=4.10

5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoic AcidEthyl Ester

Prepared by general procedure C(iii)

¹H NMR (CDCl₃) δ: 1.27 (3H, t, J=7.1 Hz), 2.02-2.06 (2H, m), 2.81-290(4H, m), 3.54 (2H, brs), 4.24 (2H, q, J=7.1 Hz), 4.95 (2H, s), 6.55 (1H,s), 6.80 (1H, d, J=8.7 Hz), 7.02-7.28 (9H, m).

LC/MS[MH+]=448 Rt=3.8.

5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-4-methanesulphonylaminobenzoicAcid Ethyl Ester

Prepared according to general procedure G

¹H NMR (CDCl₃) δ: 1.33 (3H, t, J=7.1 Hz), 2.06-2.1 (2H, m)2.62 (3H, s),2.85 (2H, t, J=7.4 Hz), 2.92 (2H, bs), 4.32 (2H, q, J=7.1 Hz), 5.04 (2H,s), 6.53 (1H, s), 7.04-7.26 (6H, m), 7.47 (1H, d, J=8.6 Hz), 7.52 (1H,s), 7.64 (1H, s), 7.64 (1H, s).

LC/MS[MH−]=577 Rt=4.14.

5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoicAcid Ethyl Ester

Prepared according to general procedure G

¹H NMR (CDCl₃) δ: 1.33 (3H, t, J=7.1 Hz), 2.04-2.09 (2H, m), 2.65 (3H,s), 2.83 (2H, t, J=7.3 Hz), 2.92 (2H, t, J=7.3 Hz), 4.32 (2H, q, J=7.1Hz), 5.09 (2H, s), 6.73-7.63 (9H, m).

LC/MS[MH−]=594 Rt=4.16.

5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoicAcid Ethyl Ester/Methyl Ester

Prepared according to general procedure G.

Product (as a mixture of methyl ester 50.7% and ethyl ester 49.3%) as ayellow oil (91%).

LC/MS[MH−]=528, 530/542, 544 Rt=3.97/4.06.

5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-acetylaminobenzoicAcid Ethyl Ester

Prepared by general procedure E.

¹H NMR (CDCl₃) δ: 1.23 (3H, q, J=7.2 Hz), 2.02-2.13 (5H, m), 2.86-2.95(4H, m), 4.22 (2H, q, J=7.1 Hz), 5.03 (2H, s), 6.95 (1H, d, J=8.6 Hz),7.09 (1H, bs), 7.20-7.30 (5H, m), 7.43 (1H, d, J=8.6 Hz), 7.47 (1H, s),7.56 (1H, s), 7.8 (1H, s).

LC/MS[MH−]=522 Rt=4.06.

5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-acetylaminobenzoicAcid Ethyl Ester

Prepared by general procedure E.

¹H NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 2.04-2.10 (2H, m), 2.12 (3H,s), 2.86 (2H, t, J=7.5 Hz), 2.96 (2H, t, J=7.4 Hz), 4.22 (2H, q, J=7.0Hz), 4.96 (2H, s), 6.93-7.03 (3H, m), 7.14-7.17 (2H, t, J=8.2), 7.33(1H, s), 7.46 (2H, bs), 7.57 (1H, s), 7.76 (1H, s).

LC/MS[MH−]=540 Rt=4.10.

5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-acetylaminobenzoicAcid Ethyl Ester

Prepared according to general procedure E.

¹H NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 2.02-2.10 (2H, m), 2.12 (3H,s), 2.85 (2H, t, J=7.4 Hz), 2.92 (2H, q, J=7.1Hz), 5.02 (2H, s),6.76-6.81 (2H, m), 6.99 (1H, d, J=8.7 Hz), 7.08-7.49 (4H, m), 7.60 (1H,s), 7.74 (1H, s).

LC/MS [MH−]=558, 559 Rt=3.8.

5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-acetylaminobenzoicAcid Ethyl Ester

Prepared according to general procedure E.

¹H NMR (CDCl₃) δ: 1.27 (3H, t, J=7.1 Hz), 2.01-2.09 (2H, m), 2.12 (3H,s), 2.84 (2H, t, J=7.5 Hz), 2.91 (2H, t, J=7.4 Hz), 4.24 (2H, q, J=7.1Hz), 4.96 (2H, s), 6.82 (1H, d, J=8.8 Hz), 7.01 (1H, s), 7.11-7.31 (6H,m), 7.51 (2H, d, J=14), 7.86 (1H, s).

LC/MS[MH−]=488, 490 Rt=4.01.

5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-acetylaminobenzoicAcid Ethyl Ester/Methyl Ester

Prepared according to general procedure E.

Product as a mixture of methyl ester and ethyl ester.

LC/MS[MH+]=510, 512 Rt=3.77 LC/MS[MH+]=526 Rt=3.86

5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-acetylaminobenzoicAcid Ethyl Ester/Methyl Ester

Prepared according to general procedure E.

Product as a mixture of methyl ester and ethyl ester.

LC/MS[MH+]=494, 496 Rt=4.0 LC/MS[MH+]=508, 510 Rt=4.09.

5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-morpholin-4-ylbenzoicAcid Ethyl Ester

Prepared according to general procedure H.

¹H NMR (CDCl₃) δ: 1.31 (3H, t, J=7.1 Hz), 2.06-2.10 (2H, m), 2.80 (4H,t, J=4.8 Hz), 2.83 (2H, t, J=7.3 Hz), 2.92 (2H, t, J=7.5 Hz), 3.70 (4H,t, J=4.8 Hz), 4.29 (2H, q, J=7.1 Hz), 5.29 (2H, s), 6.70 (1H, s),6.90-7.44 (9H, m).

LC/MS[MH+]=570, 571 Rt=4.38.

5-{2-[5-chloro-2-(-4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-morpholin-ylbenzoicAcid Ethyl Ester/Methyl Ester

Prepared according to general procedure H using as solventN-methyl-2-pyrrolidone (3 mL) instead of 2-butanone and heating at 90°C. Product obtained as a mixture of methyl ester and ethyl ester.

LC/MS [MH+]=522, 524 Rt=3.98, LC/MS[MH+]=536, 538 Rt=4.07.

5-{2-[5-trifluoromethyl-2-benzyloxyphenyl]cyclopent-1-enyl}-3-diethylaminobenzoicAcid Ethyl Ester

5-{2-[5-trifluoromethyl-2-benzyloxyphenyl]cyclopent-1-enyl}-3-aminobenzoicacid ethyl ester (90 mg, 0.18 mmol), potassium carbonate (51 mg, 0.37mmol), ethyliodide (0.037 mL, 0.47 mmol), in 3 mL of DMF were stirred at40° C. for 16 hrs, then another 0.037 mL of ethyl iodide were added andthe reaction mixture was stirred for another 4 hrs. The mixture was thenpoured into water and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried (MgSO₄), and concentrated.Purification was carried out on a SPE using a gradient ofiso-hexane/ethyl acetate.

LC/MS[MH+]=538, 539 Rt=4.55.

5-{2-[5-trifluoromethyl-2-benzyloxyphenyl]cyclopent-1-enyl}-3-methylaminobenzoicAcid Ethyl Ester

5-{2-[5-trifluoromethyl-2-benzyloxyphenyl]cyclopent-1-enyl}-3-aminobenzoicacid ethyl ester (210 mg, 0.43 mmol), sodium hydride (17 mg, 0.43 mmol),iodomethane (0.027 mL, 0.43 mmol), in 3 mL of DMF were stirred at roomtemperature for 24 hrs, then another 0.027 mL of iodomethane were addedand the reaction mixture was stirred for another 48 hrs. The mixture wasthen poured into water and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried (MgSO₄), and concentrated.Purification was carried out on SPE using iso-hexane containing agradient of ethylacetate (20-30%) to give the required product as ayellow oil. (85 mg, 39%).

LC/MS[MH+]=496 Rt=4.31.

5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methylaminobenzoicAcid Ethyl Ester

Prepared according to the procedure for5-{2-[5-trifluoromethyl-2-benzyloxyphenyl]cyclopent-1-enyl}-3-methylaminobenzoicacid ethyl ester, using 2.5 equivalents of NaH and MeI instead of 1equivalent.

LC/MS[MH+]=514, 515 Rt=4.35

5-{2-5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methylaminobenzoicAcid Ethyl Ester/Methyl Ester

Prepared according to the procedure for5{2-[5-trifluoromethyl-2-benzyloxyphenyl]cyclopent-1-enyl}-3-methylaminobenzoicacid ethyl ester, using 2.5 equivalents of NaH and MeI instead of 1equivalent.

LC/MS[MH+]=466, 468 Rt=4.17 LC/MS[MH+]=480, 482 Rt=4.34

5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(4-chlorobutanoylamino)benzoicAcid Ethyl Ester

Prepared according to general procedure J.

LC/MS[MH−]=602 Rt=4.0

5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(4-chloro-butanoylamino)benzoicAcid Ethyl Ester/Methyl Ester

Prepared according to general procedure J.

The product was a mixture of ethyl and methyl ester.

LC/MS[MH+]=556 Rt=3.94 LC/MS[MH+]=570 Rt=4.02.

5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(5-chloro-pentanoylamino)benzoicAcid Ethyl Ester

Prepared according to general procedure J using 5-chlorovaleryl chlorideinstead of 4-chlorobutyryl chloride.

¹H NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 1.84 (4H, bs), 2.04-2.09 (2H,m), 2.34 (2H, bs), 2.86-2.96 (4H, m), 3.56 (2H, bs), 4.23 (2H, q, J=7.1Hz), 5.04 (2H, s), 6.95 (1H, d, J=8.6 Hz), 7.02 (1H, s), 7.20-7.33 (5H,m), 7.44 (1H, d, J=8.6 Hz), 7.48 (1H, s), 7.58 (1H, s), 7.80 (1H, s).

5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(5-chloro-pentanoylamino)benzoicAcid Ethyl Ester

Prepared according to general procedure J using 5-chlorovaleryl chlorideinstead of 4-chlorobutyryl chloride.

LC/MS[MH−]=616 Rt=4.04

5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(5-chloro-pentanoylamino)benzoicAcid Ethyl Ester/Methyl Ester

Prepared according to general procedure J using 5-chlorovaleryl chlorideinstead of 4-chlorobutyryl chloride.

LC/MS[MH+]=570 Rt=3.98 LC/MS[MH+]=584 Rt=4.05.

5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-pyrrolidin-1-yl)benzoicAcid Ethyl Ester

Prepared according to general procedure K.

LC/MS[MH−]=566, 567 Rt=3.93

5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-pyrrolidin-1-yl)benzoicAcid Ethyl Ester/Methyl Ester

Prepared according to general procedure K.

The product was a mixture of ethyl and methyl ester.

LC/MS[MH+]=506, 508 Rt=3.84 LC/MS[MH+]=520, 522 Rt=3.93.

5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-piperidin-1-yl)benzoicAcid Ethyl Ester

Prepared according to general procedure K.

¹H NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 1.76-1.81 (4H, m), 2.04-2.10(2H, m), 2.47 (2H, t, J=6.6 Hz), 2.88 (2H, t, J=7.5 Hz), 2.95 (2H, t,J=7.5 Hz), 3.17 (2H, t, J=5.9 Hz), 4.28 (2H, q, J=7.1 Hz), 5.06 (2H, s),6.95 (1H, d, J=8.6 Hz), 7.00 (1H, s), 7.20-7.31 (6H, m), 7.44 (1H, d,J=8.6 Hz), 7.71 (2H, d, J=8.8 Hz).

5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-piperidin-1-yl)benzoicAcid Ethyl Ester/Methyl Ester

Prepared according to general procedure K.

The product was a mixture of ethyl and methyl ester.

LC/MS[MH+]=520, 522 Rt=3.67 LC/MS[MH+]=534, 536 Rt=3.78.

5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-piperidin-1-yl)benzoicAcid Ethyl Ester

Prepared according to general procedure K.

LC/MS[MH+]=582, 583 Rt=3.88

6-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicAcid Ethyl Ester

Prepared using general procedure C(iii).

LC/MS[MH+]=435, 437 Rt=4.00

6-{2-[5-chloro-2-acetoxy)phenyl]cyclopent-1-enyl}-pyrazine-2-carboxylicAcid Ethyl Ester

Prepared using general procedure F(i).

LC/MS[MH+]=387, 389 Rt=3.33

6-{2-[5-chloro-2-(hydroxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicAcid Ethyl Ester

Prepared using general procedure F(ii).

LC/MS[MH+]=345, 347 Rt=3.51

6-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-pyrazine-2-carboxylicAcid Ethyl Ester

Prepared using general procedure F(iii).

LC/MS[MH+]=471, 473 Rt=4.02

5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-morpholin-4-ylbenzoicAcid Ethyl Ester

Prepared according to general procedure H using N-methyl-2-pyrrolidone(3 mL) as solvent instead of 2-butanone and heating at 90° C.

LC/MS[MH+]=588, 589 Rt=4.29

5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-morpholinyl-4-yl-benzoicAcid Ethyl Ester/Methyl Ester

Prepared according to general procedure H using N-methyl-2-pyrrolidone(3 mL) as solvent instead of 2-butanone and heating at 90° C.

Product as a mixture of methyl ester and ethyl ester.

LC/MS[MH+]=540, 542 Rt=4.21 LC/MS[MH+]=554, 556 Rt=4.31

5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-morpholin-4-yl-benzoicAcid Ethyl Ester

Prepared according to general procedure H using N-methyl-2-pyrrolidone(3 mL) as solvent instead of 2-butanone and heating at 90° C.

LC/MS[MH+]=518, 520 Rt=4.28

5-{2-[5-trifluoromethyl-2-benzyloxyphenyl]cyclopent-1-enyl}-3-diethylaminobenzoicAcid Ethyl Ester

5-{2-[5-trifluoromethyl-2-benzyloxyphenyl]cyclopent-1-enyl}-3-aminobenzoicacid ethyl ester (90 mg, 0.18 mmol), potassium-carbonate (51 mg, 0.37mmol), ethyliodide (0.037 mL, 0.47 mmol), in 3 mL of DMF were stirred at40° C. for 16 hrs, another 0.037 mL of ethyl iodide were added and thereaction mixture was stirred for another 4 hrs. The mixture was thenpoured into water and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried (MgSO₄), and concentrated.Purification was carried out on SPE using a gradient of iso-hexane/ethylacetate.

LC/MS[MH+]=538, 539 Rt=4.55.

5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoicAcid Ethyl Ester/Methyl Ester

Prepared according to general procedure G.

Product was a mixture of methyl ester 46% and ethyl ester 54%.

LC/MS[MH−]=546, 548/560, 562 Rt=3.79/3.87

5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoicAcid Ethyl Ester

Prepared according to general procedure G.

LC/MS[MH−]=524, 526 Rt=3.85.

6-{2-[5-Methyl-2-acetoxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicAcid Ethyl Ester

Prepared by general procedure F(i) but using6-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicacid ethyl ester instead of6-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid ethyl ester.

LC/MS: Rt 3.3, [MH+] 367.4.

6-{2-[5-Methyl-2-(hydroxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicAcid Ethyl Ester

Prepared by general procedure F(ii) but using but using6-{2-[5-methyl-2-(acetoxy)phenyl]cyclopent-1-enyl}-pyrazine-2-carboxylicacid ethyl ester instead of6-[2-(5-methyl-2-acetoxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylicacid ethyl ester.

LC/MS: Rt 3.3, [MH+] 325.4.

6-{2-[5-Methyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicAcid Ethyl Ester

Prepared by general procedure F(iii) but using6-{2-[5-methyl-2-(hydroxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicacid ethyl ester instead of6-{2-[5-methyl-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid ethyl ester.

LC/MS: Rt 3.77, [MH+] 433.4

6-{2-[5-Methyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicAcid Ethyl Ester

Prepared by general procedure F(iii) but using6-{2-[5-methyl-2-(hydroxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicacid ethyl ester instead of6-{2-[5-methyl-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid ethyl ester and 2,4-difluorobenzyl bromide instead of4-fluorobenzyl bromide.

LC/MS: Rt 3.8, [MH+] 451.3

2{2-[5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-pyridine-4-carboxylicAcid Ethyl Ester

Prepared by general procedure B(iii) but using[5-trifluoromethyl-2-(2,4-diflurobenzyloxy)phenyl]boronic acid insteadof (5-chloro-2-benzyloxyphenyl)-boronic acid and2-(bromocyclopent-1-enyl)pyridine-4-carboxylic acid ethyl ester insteadof 3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester

LC/MS: Rt 4.20, [MH+] 504.1.

2{2-[5-bromo-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-4-carboxylicAcid Ethyl Ester

Prepared by general procedure B(iii) but using[5-bromo-2-(2,4-difluorobenzyloxy)phenyl]boronic acid instead of(5-chloro-2-benzyloxyphenyl)boronic acid and2-(bromocyclopent-1-enyl}-pyridine carboxylic acid ethyl ester insteadof 3-(2-bromocyclopent-1-enyl)-methylbenzoic acid ethyl ester.

¹H NMR (CDCl₃) δ: 1.28 (3H, t, J=7.16 Hz), 2.04-2.11 (2H, m), 2.89 (2H,t, J=8 Hz), 3.06 (2H, t, J=7 Hz), 4.26 (2H, q, J=7.12 Hz), 4.93 (2H, s),6.75-6.79 (2H, m), 6.83 (1H, d, J=8.8 Hz), 7.10-7.17 (1H, m), 7.25 (1H,s), 7.34 (1H, d, J=8.72 Hz), 7.47 (1H, s), 7.53 (1H, d, J=5.04 Hz), 8.60(1H, d, J=5.04 Hz).

2-{2-[5-bromo-2-(benzyloxy)phenyl]cyclopent-1-enyl}-pyridine-4-carboxylicAcid Ethyl Ester

Prepared by general procedure B(iii) but using[5-bromo-2-(benzyloxy)phenyl]boronic acid instead of(5-chloro-2-benzyloxyphenyl)boronic acid and2-(bromocyclopent-1-enyl)pyridine carboxylic-4-acid ethyl ester insteadof 3-(2-bromocyclopent-1-enyl)-6-methylbenzoic acid ethyl ester.

¹H NMR (CDCl₃) δ: 1.20-1.27 (3H, m), 2.04-2.17 (2H, m), 2.90 (2H, t,J=7.4 Hz), 3.09 (2H, t, J=7.5 Hz), 4.23 (2H, q, J=7.1 Hz), 4.95 (2H, s),6.81 (1H, d, J=8.8Hz), 7.16-7.32 (7H, m), 7.51 (1H, s), 7.54 (1H, d,J=5.0 Hz), 8.62 (1H, d, J=5.0 Hz).

3-Amino-6-(2-bromocyclopent-1-enyl)-pyrazine-2-carboxylic Acid EthylEster

Prepared by general procedure B(ii) but using3-amino-6-bromopyrazine-2-carboxylic acid ethyl ester instead of5-iodo-2-methylbenzoic acid ethyl ester.

¹H NMR (CDCl₃) δ: 1.44 (3H, t, J=7.1 Hz), 2.01-2.09 (2H, m), 2.88 (4H,t, J=7.52 Hz), 4.43 (2H, q, J=7.1 Hz), 5.99-6.94 (2H, br s), 8.80 (1H,s).

3-bromo-5-methylbenzoic Acid Ethyl Ester

Sulphuric acid (10 drops) was added to 3-bromo-5-methylbenzoic acid(1.18 g, 5.49 mmol) in ethanol (20 ml) and refluxed at 90° C. for 20hours. After cooling, the mixture was diluted with diethyl ether/waterand the organic phase washed with sodium hydrogen bicarbonate (saturatedsolution), dried (magnesium sulphate) and evaporated to dryness to givethe title compound as a pale yellow oil (1.249 g, 94%).

¹H NMR (CDCl₃) δ: 1.39 (3H, t, J=7.1 Hz), 2.39 (3H, s), 4.37 (2H, q,J=7.1 Hz), 7.51 (1H, s), 7.78 (1H, s), 7.97 (1H, s).

3-(2-bromocyclopent-1-enyl)-5-methylbenzoic Acid Ethyl Ester

Prepared by general procedure B(ii) but using 3-bromo-5-methylbenzoicacid ethyl ester instead of 5-iodo-2-methylbenzoic acid ethyl ester.

LC/MS: Rt 4.00, [MH+] 311.

3-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicAcid Ethyl Ester

Prepared by general procedure B(iii) but using[5-trifluoromethyl-2-(benzyloxy)phenyl]boronic acid instead of(5-chloro-2-benzyloxyphenyl)boronic acid and3-(2-bromocyclopent-1-enyl)-5-methylbenzoic acid ethyl ester instead of3-(2-bromocyclopent-1-enyl)-6-methylbenzoic acid ethyl ester.

¹H NMR (CDCl₃) δ: 1.25 (3H, t, J=7.1 Hz), 2.03-2.10 (2H, m), 2.18 (3H,s), 2.86-2.95 (4H, m), 4.23 (2H, q, J=7.1 Hz), 4.99 (2H, s), 6.92 (1H,d, 8.6 Hz), 7.05 (1H, s), 7.16-7.30 (5H, m), 7.34 (1H, s), 7.43 (1H, d,J=8.6 Hz), 7.61 (2H, d, J=9.9 Hz).

3-{2-[5-Chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicAcid Ethyl Ester

Prepared by general procedure B(iii) but using3-(2-bromocyclopent-1-enyl)-5-methylbenzoic acid ethyl ester instead of3-(2-bromocyclopent-1-enyl)-6-methylbenzoic acid ethyl ester.

LC/MS: Rt [MH+] 447.2

6-{2-[5-Fluoro-2-(methoxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Ethyl Ester

Prepared by general procedure B(iii) but using5-fluoro-2-methoxyphenylboronic acid instead of(5-chloro-2-benzyloxyphenyl)boronic acid and6-(2-bromocyclopent-1-enyl)-pyridine-2-carboxylic acid ethyl esterinstead of 3-(2-bromocyclopent-1-enyl)-6-methylbenzoic acid ethyl ester.

LC/MS: Rt 3.4, [MH+] 342.4.

6-{2-[5-Fluoro-2-hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

A mixture of6-{2-[5-fluoro-2-(methoxy)phenyl]cyclopent-1-enyl}-pyridine-2-carboxylicacid ethyl ester (336 mg, 0.99 mmol) and sodium methanethiolate (347 mg,4.95 mmol) in dimethyl formamide (5 ml) was heated under nitrogen at120° C. for 2.5 hours. After cooling the mixture was diluted withether/water and the aqueous separated, acidified with acetic acid andextracted with ether. The organic phase was dried (magnesium sulphate)and evaporated to yield the title compound as a yellow gum (366 mg).

LC/MS: Rt 2.53, [MH+] 300.3.

6-{2-[5-Fluoro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-pyridine-2-carboxylicAcid Benzyl Ester

Prepared by general procedure 5 but using6-{2-[5-fluoro-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid instead of6-{2-[5-chloro-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid, benzyl bromide instead of 4-chlorobenzyl bromide and with acetoneas solvent instead of 2-butanone.

LC/MS: Rt 3.96, [MH+] 480.3.

6-{2-[5-Fluoro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid 4-fluorobenzyl Ester

Prepared by general procedure 5 but using6-{2-[5-fluoro-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid instead of6-{2-[5-chloro-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid, 4-fluorobenzyl bromide instead of 4-chlorobenzyl bromide and withacetone as solvent instead of 2-butanone.

LC/MS: Rt 3.96, [MH+] 516.3.

6-{2-[5-Fluoro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid 2,4-difluorobenzyl Ester

Prepared by general procedure 5 but using6-{2-[5-fluoro-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid instead of6-{2-[5-chloro-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid, 2,4-difluorobenzyl bromide instead of 4-chlorobenzyl bromide andwith acetone as solvent instead of 2-butanone.

LC/MS: Rt 3.99, [MH+] 552.3.

6-Chloropyridazine-4-carboxylic Acid Ethyl Ester

Ethyl 2-nitro-4-furoate (990 mg, 5.35 mmol) was dissolved in ethanol (25ml) and hydrazine hydrate (0.5 g) was added and the mixture refluxed for20 minutes then cooled and evaporated to dryness. The residue wasdissolved in ether/water and the organic phase dried (magnesiumsulphate) evaporated and chromatographed on silica gel eluting withethyl acetate/iso-hexane (2:3) to give a gum (426 mg) which wasdissolved in phosphoryl chloride (4 ml) and heated at 90° C. for 30minutes. The resulting mixture was evaporated to dryness and dissolvedin ether/water and the organic phase dried (magnesium sulphate)evaporated and chromatographed twice on silica gel eluting first withethyl acetate/iso-hexane (3:17) then with methanol/dichloromethane(3:197) to give a solid which was triturated with iso-hexane andfiltered off to yield the title compound as an off-white solid. (31 mg,2.4%).

LC/MS: Rt 2.00, [MH+] 187.2, 189.2.

6-{2-[5-Chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridazine-4-carboxylicAcid Ethyl Ester

Was prepared by general procedure C(iii) but using6-chloropyridazine-4-carboxylic acid ethyl ester instead of2-chloropyrimidine-4-carboxylic acid methyl ester.

LC/MS: Rt 3.69, [MH+] 435.3.

6-{2-[5-Chloro-2-(acetoxy)phenyl]cyclopent-1-enyl}pyridazine-4-carboxylicAcid Ethyl Ester

Prepared by general method F(i) using6-{2-[5-Chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridazine-4-carboxylicacid ethyl ester instead of6-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid ethyl ester.

LC/MS: Rt 3.25, [MH+] 387.3, 389.3.

6-{2-[5-Chloro-2-(hydroxy)phenyl]cyclopent-1-enyl}-pyridazine-4-carboxylicAcid Ethyl Ester

Prepared by general procedure F(ii) but using6-{2-[5-chloro-2-(acetoxy)phenyl]cyclopent-1-enyl}pyridazine-4-carboxylicacid ethyl ester instead of6-[2-(5-methyl-2-acetoxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylicacid ethyl ester.

LC/MS: Rt 3.26, [MH+] 345.3, 347.3.

6-{2-[5-Chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-pyridazine-4-carboxylicAcid Ethyl Ester

Prepared by general procedure F(iii) but using6-{2-[5-chloro-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridazine-4-carboxylicacid ethyl ester instead of6-{2-[5-methyl-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid ethyl ester.

LC/MS: Rt 3.69, [MH+] 453.3.

6-{2-[5-Chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-pyridazine-4-carboxylicAcid Ethyl Ester

Prepared by general procedure F(iii) but using6-{2-[5-chloro-2-(hydroxy)phenyl]cyclopent-1-enyl}-pyridazine-4-carboxylicacid ethyl ester instead of6-{2-[5-methyl-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid ethyl ester and 2,4-difluorobenzyl bromide instead of4-fluorobenzyl bromide.

LC/MS: Rt 3.71, [MH+] 471.3, 473.3.

5-{2-[-5-chloro-2-(2,4-difluorobenzyloxy)phenyl)cyclopent-1-enyl]-2-methylbenzoicAcid t-butyl Ester

The title compound was prepared using general procedure B(iii) using3-(2-bromocyclopent-1-enyl)-6-methyl benzoic acid t-butyl ester to givethe product as a yellow oil 40 mg 22%.

¹HNMR (CDCl₃): ) δ: 1.49 (9H, s), 2.02-2.05 (2H, m), 2.47 (3H, s), 2.80(2H, t, J=6 Hz), 2.91 (2H, t, J=6 Hz), 4.91 (2H, s), 6.50-7.16 (8H, m),7.57 (1H, s).

3-(2-bromocyclopent-1-enyl)-6-methylbenzoic Acid t-butyl Ester

The title compound was prepared according to general procedure B(ii)using 5-iodo-2-methylbenzoic acid t-butyl ester to give the product as ayellow oil 120 mg 38%.

¹HNMR (CDCl₃): δ: 1.55 (9H, s), 2.02-2.06 (2H, m), 2.56 (3H, s),2.74-2.76 (2H, m), 2.83-2.87 (2H, m), 7.20 (1H, d, J=8 Hz), 7.61 (1H, d,J=8 Hz), 8.07 (1H, s).

5-iodo-2-methylbenzoic Acid t-butyl Ester

A mixture of 5-iodo-2-methylbenzoic acid (760 mg, 2.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (670 mg, 3.5mmol), 4-dimethylaminopyridine (425 mg, 3.5 mmol), and t-butanol (1.07g, 14.5 mmol) in dichloromethane (10 ml) was stirred at room temperatureovernight. The reaction mixture was diluted with ethyl acetate (25 ml)and washed with 5% NaHCO₃, 1M HCl, water and, brine. The organic phasewas dried and evaporated to give a pale yellow solid 600 mg 65%.

¹H NMR (CDCl₃): δ: 1.58 (9H, s), 2.49 (3H, s), 6.95 (1H, d, J=8 Hz), 7.6(1H, d, J=8 Hz), 8.10 (1H, s).

5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl}cyclopent-1-enyl}-2-methylbenzoicAcid t-butyl Ester

The title compound was prepared using general procedure B(iii) using3-(2-bromocyclopent-1-enyl)-6-methyl benzoic acid t-butyl ester to givethe product as a yellow oil 60 mg 21%.

¹HNMR (CDCl₃): δ: 1.49 (9H, s), 2.00-2.05 (2H, m), 2.48 (3H, s), 2.81(2H, t, J=6 Hz), 2.89 (2H, t, J=6 Hz), 4.86 (2H, s), 6.79 (1H, d, J=8Hz), 6.94-7.13 (8H, m), 7.59 (1H, s).

5-[2-(5-chloro-2-(4-fluorobenzyloxy)phenyl)cyclopent-1-enyl]-2-fluorobenzoicAcid Ethyl Ester

Prepared according to general procedure C(iii) using ethyl5-bromo-2-fluorobenzoate and2-(2-(4-fluorobenzyloxy)-5-chlorophenyl)cyclopentene-1-boronic acid togive the product as a colourless solid 43 mg 23%.

LC/MS: Rt=4.10 [M+H] 469 (1 Cl).

5-[2-(2-benzyloxy)-5-chlorophenyl)cyclopent-1-enyl]-2-fluorobenzoic AcidEthyl Ester

Prepared according to general procedure C(iii) using ethyl5-bromo-2-fluorobenzoate and2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid to give theproduct as a colourless oil 61 mg 37%.

LC/MS: Rt=4.13 [M+H] 451 (1 Cl).

4-(2-Bromocyclopent-1-enyl)benzoic Acid Ethyl Ester

Prepared by general procedure 1(a(ii)).

¹H NMR (400 MHz, CDCl₃) δ: 1.36-1.44 (3H, t, J=7 Hz), 2.02-2.11 (2H, m),2.75-2.82 (2H, m), 2.84-2.91 (2H, m), 4.35-4.42 (2H, q, J=7 Hz),7.64-7.69 (2H, m), 8.00-8.06 (2H, m).

LC/MS [MH+] 297 Rt=3.68 min.

5-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-nicotinicAcid Ethyl Ester

Prepared according to general procedure 8.

Product 22 mg, 30%.

¹H NMR (400 MHz, CDCl₃) δ: 1.33 (3H, t, J=7 Hz), 2.07-2.16 (2H, m),2.87-2.99 (4H, m), 4.27-4.35 (2H, q, J=7.5 Hz), 5.00 (2H, s), 6.97 (1H,d, J=9 Hz), 7.17 (2H, dd, J=6 Hz), 7.26-7.34 (4H, m), 7.47 (1H, dd, J=8Hz), 7.94 (1H, t, J=4Hz), 8.42 (1H, d, J=2 Hz), 8.93-(1H, d, J=2 Hz).

4-{2-[2-(Benzyloxy)phenyl]cyclopent-1-enyl}-benzoic Acid Ethyl Ester

Prepared by general procedure B(iii).

¹H NMR (400 MHz, CDCl₃) δ: 1.32-1.38 (3H, t, J=7 Hz), 2.02-2.12 (2H, m),2.86-2.96 (4H, m), 4.28-4.36 (2H, q, J=7 Hz), 5.00 (2H, s), 6.82-6.87(1H, m), 6.90 (1H, d, J=8 Hz), 6.97-7.02 (1H, m), 7.14-7.17 (2H, m),7.17-7.35 (6H, m), 7.76-7.81 (2H, m).

4-[2-(2-Benzyloxy-5-chlorophenyl)cyclopent-1-enyl]benzoic Acid EthylEster

Prepared by general procedure B(iii).

¹H NMR (400 MHz, CDCl₃) δ: 1.37 (3H, t, J=7 Hz) 2.01-2.12 (2H, m),2.82-2.96 (4H, m), 4.33 (2H, q, J=7 Hz), 4.94 (2H, s), 6.82 (1H, d, J=9Hz), 7.00 (1H, d, J=3 Hz), 7.10-7.22 (5H, m), 7.24-7.34 (3H, m), 7.82(2H, d, J=9 Hz).

3-{2-[5-Chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicAcid Ethyl Ester

Prepared by general procedure B(iii) but using3-(2-bromocyclopent-1-enyl)-5-methylbenzoic acid ethyl ester instead of3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester and using[5-chloro-2-(4-fluorobenzyloxy)phenyl]boronic acid instead of(5-chloro-2-benzyloxyphenyl)boronic acid.

¹NMR (CDCl₃) δ: 1.30 (3H, t, J=7.1 Hz), 2.06 (2H, m), 2.21 (3H, s),2.81-2.93 (4H, m), 4.27 (2H, q, J=7.1 Hz), 4.86 (2H, s), 6.79 (1H, d,J=8.8 Hz), 6.94-7.26 (7H, m), 7.60 (2H, m).

3-{2-[5-Chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicAcid Ethyl Ester

Prepared by general procedure B(iii) but using3-(2-bromocyclopent-1-enyl)-5-methylbenzoic acid ethyl ester instead of3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester and using[5-chloro-2-(2,4-di-fluorobenzyloxy)phenyl]boronic acid instead of(5-chloro-2-benzyloxyphenyl)boronic acid.

¹H NMR (CDCl₃) δ: 1.31 (3H, t, J=7.2 Hz), 2.01-2.09 (2H, m), 2.21 (3H,s), 2.80-2.93 (4H, m), 4.27 (2H, q, J=7.1 Hz), 4.91 (2H, s), 6.74-6.84(3H, m), 7.04-7.17 (4H, m), 7.59 (2H, m).

3-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicAcid Ethyl Ester

Prepared by general procedure B(iii) but using3-(2-bromocyclopent-1-enyl)-5-methylbenzoic acid ethyl ester instead of3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic add ethyl ester and using[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]boronic acid instead of(5-chloro-2-benzyloxyphenyl)boronic acid.

¹H NMR (CDCl₃) δ: 1.27 (3H, t, J=7.1 Hz), 2.03-2.11 (2H, m), 2.19 (3H,s), 2.84-2.95 (4H, m), 4.25 (2H, q, J=7.1 Hz), 4.94 (2H, s), 6.91-7.02(3H, m), 7.11-7.14 (2H, m), 7.26 (1H, s), 7.35 (1H, s), 7.45 (1H, d,J=8.6 Hz), 7.55 (1H, s), 7.61 (1H, s).

3-{2-[5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicAcid Ethyl Ester

Prepared by general procedure B(iii) but using3-(2-bromocyclopent-1-enyl)-5-methylbenzoic acid ethyl ester instead of3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester and using[5-trifluoromethyl-2-(2,4-di-fluorobenzyloxy)phenyl]boronic acid insteadof (5-chloro-2-benzyloxyphenyl)boronic acid.

¹H NMR (CDCl₃) δ: 1.28 (3H, t, J=7.1 Hz), 2.03-2.11 (2H, m), 2.19 (3H,s), 2.83-2.95 (4H, m), 4.25 (2H, q, J=7.1 Hz), 5.00 (2H, s), 6.76-6.81(2H, m), 6.95-7.01 (3H, m), 7.35 (1H, s), 7.46-7.49 (1H, m), 7.54 (1H,s), 7.60 (1H, s).

3-bromo-5-fluorobenzoic Acid Ethyl Ester

Sulphuric acid (5 drops) was added to 3-bromo-5-fluorobenzoic acid(1.194 g, 5.45 mmol) in ethanol (10 ml) and refluxed with stirring at90° C. for 17 hours. Reaction mixture partitioned between diethyl etherand water, washed with sodium hydrogen carbonate, dried (MgSO₄) andevaporated to dryness.

¹H NMR (CDCl₃) δ: 1.40 (3H, t, J=7.2 Hz), 4.39 (2H, q, J=7.1 Hz),7.42-7.45 (1H, m), 7.66-7.69 (1H, m), 7.98 (1H, s).

3-(2-bromocyclopent-1-enyl)-5-fluorobenzoic Acid Ethyl Ester

Prepared by general procedure B(ii) but using 3-bromo-5-fluorobenzoicacid ethyl ester instead of 5-iodo-2-methylbenzoic acid ethyl ester

LC/MS: Rt 4.01, [MS+] 313.0

3-{2-[5-Chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoicAcid Ethyl Ester

Prepared by general procedure B(iii) but using3-(2-bromocyclopent-1-enyl)-5-fluorobenzoic acid ethyl ester instead of3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester.

¹H NMR (CDCl₃) δ: 1.31 (3H, t, J=7.2 Hz), 2.03-2.10 (2H, m), 2.83-2.93(4H, m), 4.28 (2H, q, J=7.1 Hz), 4.95 (2H, s), 6.83-6.85 (1H, m),6.92-6.94 (1H, m), 7.02 (1H, s), 7.13-7.19 (3H, m), 7.26-7.32 (3H, m),7.45-7.47 (1H, m), 7.60 (1H, s).

3-{2-[5-Chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoicAcid Ethyl Ester

Prepared by general procedure B(iii) but using3-(2-bromocyclopent-1-enyl)-5-fluorobenzoic acid ethyl ester instead of3-(2-bromo-cyclopent-1-enyl)-6-methylbenzoic acid ethyl ester and using[5-chloro-2-(4-fluorobenzyloxy)phenyl]boronic acid instead of(5-chloro-2-benzyloxyphenyl)boronic acid.

¹H NMR (CDCl₃) δ: 1.32 (3H, t, J=7.1 Hz), 2.02-2.10 (2H, m), 2.82-2.92(4H, m), 4.29 (2H, q, J=7.1 Hz), 4.88 (2H, s), 6.82 (1H, m), 6.91 (1H,m), 6.95-7.18 (6H, m), 7.45-7.48 (1H, m), 7.58 (1H, s).

3-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-fluorobenzoicAcid Ethyl Ester

Prepared by general procedure B(iii) but using3-(2-bromocyclopent-1-enyl)-5-fluorobenzoic acid ethyl ester instead of3-(2-bromo-cyclopent-1-enyl)-6-methylbenzoic acid ethyl ester and using[5-chloro-2-(2,4-di-fluorobenzyloxy)phenyl]boronic acid instead of(5-chloro-2-benzyloxyphenyl)boronic acid.

¹H NMR (CDCl₃) δ: 1.32 (3H, t, J=7.1 Hz), 2.02-2.10 (2H, m), 2.80-2.92(4H, m), 4.29 (2H, q, J=7.1 Hz), 4.93 (2H, s), 6.78-6.91 (4H, m), 7.05(1H, s), 7.10-7.17 (1H, m), 7.18-7.21 (1H, m), 7.44-7.47 (1H, m), 7.56(1H, s).

3-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoicAcid Ethyl Ester

Prepared by general procedure B(iii) but using3-(2-bromocyclopent-1-enyl)-5-fluorobenzoic acid ethyl ester instead of3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester and using[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]boronic acid instead of(5-chloro-2-benzyloxyphenyl)boronic acid.

¹H NMR (CDCl₃) δ: 1.28 (3H, t, J=7.1 Hz), 2.04-2.12 (2H, m), 2.85-2.93(4H, m), 4.27 (2H, t, J=7.1 Hz), 4.95 (2H, s), 6.88-7.01 (4H, m),7.12-7.15 (2H, m), 7.35 (1H, s), 7.45-7.54 (2H, m), 7.54 (1H, s).

3-{2-[5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoicAcid Ethyl Ester

Prepared by general procedure B(iii) but using3-(2-bromocyclopent-1-enyl)-5-fluorobenzoic acid ethyl ester instead of3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester and using[5-trifluoromethyl-2-(2,4-di-fluorobenzyloxy)phenyl]boronic acid insteadof 5-chloro-2-benzyloxyphenyl)boronic acid.

¹H NMR (CDCl₃) δ: 1.27 (3H, t, J=7.1 Hz), 2.04-2.12 (2H, m), 2.83-2.93(4H, m), 4.27 (2H, q, J=7.1 Hz), 5.01 (2H, s), 6.78-6.89 (3H, m),6.99-7.01 (1H, m), 7.10-7.15 (1H, m), 7.34 (1H, s), 7.44-7.52 (3H, m).

2-{2-[5-Bromo-2-(4-fluorobenzyloxy)phenyl]-cyclopent-1-enyl}-isonicotinicAcid Ethyl Ester

Prepared according to standard procedure B(iii) to give the product as ayellow gum 45 mg 27%

LC/MS: Rt=3.92 [M+H] 496, 498 (1 Br)

6-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Ethyl Ester

Prepared using general procedure F(iii).

LC/MS[MH+]=434, 436 Rt=4.12

6-{2-[5-chloro-2-(4-bromobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Ethyl Ester

Prepared using general procedure F(iii).

LC/MS[MH+]=514, 516 Rt=4.29.

6-{2-[5-chloro-2-(2-chloro-4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Ethyl Ester

Prepared using general procedure F(iii).

LC/MS[MH+]=486, 489 Rt=4.30.

6-{2-[5-chloro-2-(2,4,6-trifluorobenzyloxy)phenyl]cyclopent-1-enyl}-pyridine-2-carboxylicAcid Ethyl Ester

Prepared using general procedure F(iii).

LC/MS[MH+]=488, 490 Rt=4.12.

6-{2-[5-chloro-2-(2,6-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Ethyl Ester

Prepared using general procedure F(iii).

LC/MS[MH+]=470, 472 Rt=4.09.

6-{2-[5-chloro-2-(4-trifluoromethyl-2-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Ethyl Ester

Prepared using general procedure F(iii).

LC/MS[MH+]=520, 522 Rt=4.30.

6-{2-[5-chloro-2-(3,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Ethyl Ester

Prepared using general procedure F(iii).

LC/MS[MH+]=470, 472 Rt=4.16.

6-{2-[5-chloro-2-(2,3-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Ethyl Ester

Prepared using general procedure F(iii).

LC/MS[MH+]=470, 472 Rt=4.14.

6-{2-[5-chloro-2-(4-methylbenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Ethyl Ester

Prepared using general procedure F(iii).

LC/MS[MH+]=448, 450 Rt=4.22.

6-{2-[5-chloro-2-(4-trifluoromethylbenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Ethyl Ester

Prepared using general procedure F(iii).

LC/MS[MH+]=502, 504 Rt=4.26.

2-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4-carboxylicAcid Ethyl Ester

Prepared by general procedure C(iii) but using2-[2-(benzyloxy)-5-trifluoromethylphenyl]cyclopentene-1-boronic acidinstead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid.

LC/MS: Rt 3.78, [MH+] 469.3.

3-{2-[5-Methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-acetamidobenzoicAcid Ethyl Ester

Prepared by general procedure E but using3-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoic acidethyl ester and acetyl chloride.

LC/MS: Rt 4.01, [MH+] 470.4.

3-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-fluorobenzoicAcid Ethyl Ester

Prepared by general procedure C(iii) but using2-(2-benzyloxy-5-trifluoromethylphenyl)cyclopentene-1-boronic acidinstead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid and3-bromo-6-fluorobenzoic acid ethyl ester instead of2-chloropyrimidine-4-carboxylic acid methyl ester.

¹H NMR (CDCl₃) δ: 1.28 (3H, t), 2.05-2.12 (2H, m), 2.86-2.94 (4H, m),4.28 (2H, q) 5.02 (2H, s), 6.85 (1H, dd, J=9 Hz, 3 Hz), 6.96 (1H, d, J=9Hz), 7.19-7.32 (6H, m), 7.33 (1H, s), 7.45 (1H, d, J=9 Hz), 7.66 (1H, d,J=9 Hz).

3-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-methylbenzoicAcid Ethyl Ester

Prepared by general procedure B(iii) but using2-[5-trifluoromethyl-2-(benzyloxy)phenyl]boronic acid instead of(5-chloro-2-benzyloxyphenyl)boronic acid.

¹H NMR (d₆DMSO) δ: 1.12 (3H, t), 2.00-2.03 (2H, m), 2.43 (3H, s).2.83-2.88 (4H, m), 4.10 (2H, q) 5.14 (2H, s), 7.16-7.34 (9H, m), 7.52(1H, s), 7.62 (1H, d, J=9 Hz).

5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-5-chloropentanoylamino)benzoicAcid Ethyl Ester/Methyl Ester

Prepared according to general procedure J using 5-chlorovaleryl chlorideinstead of 4-chlorobutyryl chloride.

LC/MS[MH−]=586, 588 Rt=3.98 LC/MS[MH−]=602, 604 Rt=4.05

5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(5-chloropentanoylamino)benzoicAcid Ethyl Ester

Prepared according to general procedure J using 5-chlorovaleryl chlorideinstead of 4-chlorobutyryl chloride.

LC/MS[MH−]=564 Rt=4.02.

5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-5-chloropentanoylamino)benzoicAcid Ethyl Ester

Prepared according to general procedure J using 5-chlorovaleryl chlorideinstead of 4-chlorobutyryl chloride.

LC/MS[MH−]=634 Rt=3.94

5-{2-[5-trifluoromethyl-2-(2,4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(4-chlorobutanoylamino)benzoicAcid Ethyl Ester

Prepared according to general procedure J.

LC/MS[MH−]=620 Rt=4.00.

5-{2-[5-chloro-2-(2,4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(4-chlorobutanoylamino)benzoicAcid Ethyl Ester/Methyl Ester

Prepared according to general procedure J.

LC/MS[MH+]=574 (2Cl) Rt=3.92 LC/MS[MH+]=588 (2Cl) Rt=3.99.

5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(4-chlorobutanoylamino)benzoicAcid Ethyl Ester

Prepared according to general procedure J.

LC/MS[MH+]=552 (2Cl) Rt=3.97.

5-{2-[5-chloro-2-(2,4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopyrrolidin-1-yl)benzoicAcid Ethyl Ester/Methyl Ester

Prepared according to general procedure K.

The product was a mixture of ethyl and methyl ester.

LC/MS[MH+]=538, 540 Rt=3.81 LC/MS[MH+]=552, 554 Rt=3.89.

5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopyrrolidin-1-yl)benzoicAcid Ethyl Ester

Prepared according to general procedure K.

LC/MS[MH+]=516, 518 Rt=3.92.

5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopyrrolidin-1-yl)benzoicAcid Ethyl Ester

Prepared according to general procedure K.

LC/MS[MH−]=586 Rt=3.94.

5-{2-[5-chloro-2-(2,4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopiperidin-1-yl)benzoicAcid Ethyl Ester/Methyl Ester

Prepared according to general procedure K.

The product was a mixture of ethyl and methyl ester.

LC/MS[MH+]=552, 554 Rt=4.0 LC/MS[MH+]=566, 568 Rt=4.09.

5-{2-5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopiperidin-1-yl)benzoicAcid Ethyl Ester

Prepared according to general procedure K.

LC/MS[MH+]=530, 532 Rt=3.86.

5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopiperidin-1-yl)benzoicAcid Ethyl Ester

Prepared according to general procedure K.

LC/MS[MH+]=600, 601 Rt=4.11

Example 442-{2-[5-Chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃)δ: 2.12-2.18 (2H, m), 2.96 (2H, t, J=8 Hz), 3.11 (2H, t,J=8 Hz), 4.94 (2H, s), 6.94 (1H, d, J=9 Hz), 7.10-7.14 (3H, m),7.23-7.27 (4H, m), 7.69 (1H, d, J=5 Hz), 8.90 (1H, d, J=5 Hz).

LC/MS Rt 3.74, [MH+] 407.3, 409.4.

Example 456-{2-[5-Methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃)δ: 2.10-2.15 (2H, m), 2.26 (3H, s), 2.92-2.96 (2H, m),3.00-3.04 (2H, m), 4.92 (2H, s), 6.88 (1H, d, J=8 Hz), 6.94 (1H, d, J=2Hz), 7.06-7.15 (2H, m), 7.22-730 (5H, m), 7.67, (1H, t, J=8 Hz), 7.86(1H, d, J=8 Hz).

LC/MS: Rt 3.3 [MH+π 386.4.

Example 466-{2-[5-Methyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃)δ: 2.07-2.15 (2H, m), 2.26 (3H, s), 2.90-2.93 (2H, m),2.99-3.03 (2H, m), 4.87 (2H, s), 6.87-6.95 (4H, m), 7.07-7.12 (3H, m),7.29 (1H, d, J=8 Hz), 7.69 (1H, t, J=8 Hz), 7.87 (1H, d, J=8 Hz).

LC/MS: Rt 3.4 [MH+] 404.3.

Example 476-{2-[5-Methyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃)δ: 2.07-2.14 (2H, m), 2.26 (3H, s), 2.88-2.92 (2H, m),2.98-3.03 (2H, m), 4.92 (2H, s), 6.70-6.74 (2H, m), 6.91-6.94 (2H, m),7.09-7.14 (2H, m), 7.28 (1H, d, J=8 Hz), 7.68 (1H, t, J=8 Hz), 7.87 (1H,d, J=8 Hz).

LC/MS: Rt 3.4 [MH+] 422.3.

Example 482-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-4-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (DMSO-d₆) δ: 1.99-2.03 (2H, m), 2.87-2.90 (2H, m), 2.98-3.02 (2H,m), 5.08 (2H, s), 7.10-7.22 (4H, m), 7.26 (1H, d, J=9 Hz), 7.37-7.39(2H, m), 7.52 (1H, dd, J=5 Hz, 1 Hz), 7.62-7.64 (1H, dd, J=9 Hz, 1 Hz),8.59 (1H, d, J=5 Hz), 13.3 (1H, br s).

LC/MS: Rt 3.92 [MH+] 458.0.

Example 492-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-pyridine-4-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (DMSO-d₆) δ: 1.98-2.05 (2H, m), 2.88-2.92 (2H, m), 2.99-3.02 (2H,m), 5.11 (2H, s), 7.16-7.17 (2H, m), 7.26-7.30 (4H, m), 7.38-7.40 (2H,m), 7.53 (1H, dd, J=5 Hz, 1 Hz), 7.62-7.64 (1H, dd, J=9 Hz, 1 Hz), 8.60(1H, d, J=5 Hz) 13.3 (1H, br s).

LC/MS: Rt 3.90 [MH+] 440.0.

Example 504-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (DMSO-d₆) δ: 2.01-2.05 (2H, m), 2.86-2.92 (4H, m), 5.09 (2H, s),7.11-7.40 (7H, m), 7.63-7.68 (2H, m), 8.46 (1H, d, J=5 Hz), 13.1 (1H, brs).

LC/MS: Rt 3.55 [MH+] 458.0.

Example 514-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (DMSO-d₆) δ: 2.00-2.07 (2H, m), 2.86-2.92 (4H, m), 5.13 (2H, s),7.15-7.19 (3H, m), 7.30-7.38 (5H, m), 7.63-7.67 (2H, m), 8.46 (1H, d,J=5 Hz), 13.2 (1H, br s).

LC/MS: Rt 3.52 [MH+] 440.0.

Example 526-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-aminopyrazine-2-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (DMSO-d₆) δ: 1.95-2.02 (2H, m), 2.85-2.88 (2H, m), 2.93-2.97 (2H,m), 5.13 (2H, s), 7.18-7.20 (2H, m), 7.25-7.32 (6H, m), 7.42 (1H, d, J=2Hz), 7.62 (1H, dd, J=8 Hz, 2 Hz), 7.69 (1H, s), 12.7 (1H, br s).

LC/MS: Rt 3.94 [MH+] 456.1.

Example 532-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (DMSO-d₆) δ: 2.00-2.09 (2H, m), 2.90-2.94 (2H, m), 3.02-3.06 (2H,m), 4.99 (2H, s), 7.07-7.19 (5H, m), 7.46 (1H, d, J=2 Hz), 7.57-7.61(2H, m), 8.74 (1H, d, J=5 Hz), 13.4 (1H, br s).

LC/MS: Rt 3.7 [MH+] 459.3.

Example 542-{2-[5-Chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃)δ: 2.11-2.17 (2H, m), 2.92-2.96 (2H, m), 3.10-3.14 (2H,m), 4.90 (2H, s), 6.91-6.95 (3H, m), 7.08-7.14 (3H, m), 7.27 (1H, m),7.71 (1H, d, J=5 Hz), 8.91 (1H, d, J=5 Hz).

LC/MS: Rt 3.8 [MH+] 425.3, 427.3.

Example 556-{2-[5-Methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ 2.13-2.18 (2H, m), 2.27 (3H, s), 2.96-3.00 (2H, m),3.02-3.06 (2H, m), 4.89 (2H, s), 6.90 (1H, d, J=9 Hz), 6.96 (1H, d, J=2Hz), 7.10-7.12 (3H, m), 7.23-7.26 (3H, m), 8.54 (1H, s), 8.99 (1H, s).

LC/MS: Rt 3.7 [MH+] 387.4.

Example 563-{2[5-Methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoic Acid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃)δ: 1.99-2.06 (2H, m), 2.20 (3H, s), 2.83-2.90 (4H, m),4.98 (2H, s), 6.37 (1H, d, J=9 Hz), 6.81 (1H, d, J=8 Hz), 6.89 (1H, s),6.97 (1H, d, J=7 Hz), 7.03 (1H, dd, J=9 Hz, 2 Hz), 7.25-7.32 (5H, m),7.79 (1H, d, J=2 Hz).

LC/MS: Rt 3.8 [MH+] 400.4.

Example 576-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (DMSO-d₆) δ: 2.00-2.04 (2H, m), 2.88-2.91 (2H, m), 3.00-3.04 (2H,m), 5.12 (2H, s), 7.04 (1H, d, J=7 Hz), 7.17-7.19 (2H, m), 7.26-7.32(4H, m), 7.36 (1H, d, J=2 Hz), 7.61 (1H, dd, J=9 Hz, 2 Hz), 7.67 (1H, t,J=8 Hz), 7.78 (1H, d, J=7 Hz), 12.8 (1H, br s).

LC/MS: Rt 3.87 [MH+] 440.0.

Example 586-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (DMSO-d₆) δ: 1.99-2.03 (2H, m), 2.86-2.90 (2H, m), 3.00-3.04 (2H,m), 5.09 (2H, s), 7.04 (1H, d, J=7 Hz), 7.17-7.19 (2H, t, J=9 Hz),7.22-7.29 (3H, m), 7.38 (1H, d, J=2 Hz), 7.62 (1H, dd, J=9 Hz, 2 Hz),7.67 (1H, t, J=8 Hz), 7.78 (1H, d, J=7 Hz), 13.3 (1H, br s).

LC/MS: Rt 3.88 [MH+] 458.1.

Example 596-{2-[5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (DMSO-d₆) δ: 1.95-2.02 (2H, m), 2.82-2.86 (2H, m), 2.97-3.01 (2H,m), 5.12 (2H, s), 6.99-7.02 (2H, m), 7.23-7.37 (4H, m), 7.66 (2H, t, J=8Hz), 7.75 (1H, d, J=8 Hz), 12.9 (1H, br s).

LC/MS: Rt 3.91 [MH+] 476.1.

Example 603-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (DMSO-d₆) δ: 1.94-1.97 (2H, m), 2.75-2.83 (4H, m), 5.16 (2H, s),6.49 (1H, d, J=9 Hz), 6.86 (1H, dd, J=9 Hz, 2 Hz), 7.22-7.34 (7H, m),7.55-7.58 (2H, m).

LC/MS: Rt 3.8 [MH+] 454.4.

Example 613-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (DMSO-d₆) δ: 1.93-1.97 (2H, m), 2.75-2.81 (4H, m), 5.13 (2H, s),6.49 (1H, d, J=9 Hz), 6.86 (1H, dd, J=9 Hz, 2 Hz), 7.14 (2H, t, J=9 Hz),7.22-7.31 (4H, m), 7.53 (1H, d, J=2 Hz), 7.57 (1H, dd, J=9 Hz, 2 Hz).

LC/MS: Rt 3.8 [MH+] 472.4.

Example 623-{2-[5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (DMSO-d₆) δ: 1.88-1.96 (2H, m), 2.71-2.79 (4H, m), 5.17 (2H, s),6.47 (1H, d, J=9 Hz), 6.82 (1H, dd, J=9 Hz, 2 Hz), 7.05 (2H, dt, J=9 Hz,2 Hz), 7.25-7.32 (3H, m), 7.49 (1H, d, J=2 Hz), 7.60 (1H, dd, J=9 Hz, 2Hz).

LC/MS: Rt 3.8 [MH+] 490.4.

Example 633-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-acetamidobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (DMSO-d₆) δ: 1.97-2.04 (2H, m), 2.10 (3H, s), 2.81-2.89 (4H, m),5.15 (2H, s), 7.21-7.33 (8H, m), 7.60 (1H, dd, J=9 Hz, 2 Hz), 7.72 (1H,d, J=2 Hz), 8.25 (1H, d, J=9 Hz), 10.95 (1H, s), 13.4 (1H, br s).

LC/MS: Rt 3.9 [MH+] 496.4.

Example 643-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-acetamidobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (DMSO-d₆) δ: 1.96-2.03 (2H, m), 2.10 (3H, s), 2.79-2.88 (4H, m),5.11 (2H, s), 7.11-7.27 (6H, m), 7.34 (1H, d, J=2 Hz), 7.60 (1H, dd, J=9Hz, 2 Hz), 7.69 (1H, d, J=2 Hz), 8.23 (1H, d, J=9 Hz), 10.95 (1H, s),13.4 (1H, br s).

LC/MS: Rt 3.9 [MH+] 514.3.

Example 653-{2-5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-acetamidobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (DMSO-d₆) δ: 1.93-2.01 (2H, m), 2.10 (3H, s), 2.75-2.86 (4H, m),5.14 (2H, s), 7.03 (1H, dt, J=8 Hz, 2 Hz), 7.16-7.36 (5H, m), 7.63 (1H,dd, J=9 Hz, 2 Hz), 7.65 (1H, d, J=2 Hz), 8.21 (1H, d, J=9 Hz), 10.95(1H, s), 13.4 (1H, brs).

LC/MS: Rt 3.9 [MH+] 532.0.

Example 663-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃)δ: 1.21 (3H, t, J=8 Hz), 2.05-2.12 (2H, m), 2.31-2.36 (2H,m), 2.87-2.94 (4H, m), 5.05 (2H, s), 6.95 (1H, s), 6.97 (1H, s),7.23-7.34 (6H, m), 7.44 (1H, d, J=8 Hz), 7.53 (1H, s), 7.57 (1H, s),7.90 (1H, s).

LC/MS: Rt 3.7 [MH−] 508.1.

Example 673-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃)δ: 1.22 (3H, t, J=8 Hz), 2.04-2.11 (2H, m), 2.32-2.37 (2H,m), 2.85-2.95 (4H, m), 4.98 (2H, s), 6.93-7.02 (4H, m), 7.19 (2H, t, J=8Hz), 7.32 (1H, s), 7.45 (1H, d, J=8 Hz), 7.50 (1H, s), 7.62 (1H, s),7.85 (1H, s).

LC/MS: Rt 3.7 [MH−] 526.2.

Example 683-{2-[5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃)δ: 1.22 (3H, t, J=8 Hz), 2.03-2.10 (2H, m), 2.32-2.37 (2H,m), 2.83-2.87 (2H, m), 2.91-2.95 (2H, m), 5.04 (2H, s), 6.77-6.84 (2H,m), 6.99 (1H, d, J=9 Hz), 7.04 (1H, s), 7.19 (1H, q, J=8 Hz), 7.32 (1H,s), 7.46-7.49 (2H, m), 7.65 (1H, s), 7.83 (1H, s).

LC/MS: Rt 3.7 [MH−] 544.1.

Example 693-{2-[5-Bromo-2-(benzyloxy)phenyl]cyclopent-1-enyl})-5-propionamidobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃)δ: 1.23 (3H, t, J=8 Hz), 2.03-2.10 (2H, m), 2.32-2.38 (2H,m), 2.83-2.87 (2H, m), 2.91-2.95 (2H, m), 4.96 (2H, s), 6.77 (1H, d, J=9Hz), 6.98 (1H, s), 7.15 (1H, s), 7.21-7.30 (6H, m), 7.50 (1H, s), 7.56(1H, s), 7.97 (1H, s).

LC/MS: Rt 3.94 [MH−] 518.0, 520.0.

Example 703-{2-[5-Bromo-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 1.23 (3H, t, J=8 Hz), 2.01-2.09 (2H, m), 2.32-2.39(2H, m), 2.81-2.84 (2H, m), 2.89-2.95 (2H, m), 4.90 (2H, s), 6.76 (1H,d, J=9 Hz), 6.98 (3H, m), 7.12-7.29 (4H, m), 7.54 (1H, s), 7.55 (1H, s),7.92 (1H, s).

LC/MS: Rt 3.91 [MH−] 536.0, 538.0.

Example 713-{2-[5-Bromo-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃)δ: 1.21 (3H, t, J=8 Hz), 2.01-2.09 (2H, m), 2.32-2.39 (2H,m), 2.80-2.84 (2H, m), 2.89-2.93 (2H, m), 4.96 (2H, s), 6.75-6.83 (3H,m), 7.03 (1H, s), 7.13-7.25 (2H, m), 7.27-7.32 (1H, m), 7.53 (1H, s),7.59 (1H, s), 7.90 (1H, s).

LC/MS: Rt 3.98 [MH−] 554.0, 556.0.

Example 725-{2-[Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}nicotinicAcid N-oxide

3-Chloroperbenzoic acid (25 mg, 0.11 mmol) was added to a solution of5-{2-[trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}nicotinicacid (44 mg, 0.1 mmol) in dioxan (2 ml) and left overnight at roomtemperature. The resulting mixture was evaporated to dryness andpurified by preparative mass directed chromatography to give the titlecompound as an off-white solid (8 mg, 18%).

¹H NMR (DMSO-d₆) δ: 1.97-2.06 (2H, m), 2.84-2.90 (4H, m), 5.16 (2H, s),7.23-7.35 (7H, m), 7.46 (1H, s), 7.67 (1H, dd J=9 Hz, 2 Hz), 8.01 (1H,s), 8.25 (1H, s), 13.7 (1H, br s).

LC/MS: Rt 3.82 [MH+] 456.1.

Example 735-{2-[5-fluoro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(propionamido)benzoicAcid

The title compound was prepared from5-{2-[5-fluoro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(propionamido)benzoic acid 4-fluorobenzylester following the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 1.21-1.28 (3H,m), 2.03-2.06 (2H, m), 2.36-2.45 (2H,m), 2.84-2.89 (4H, m), 4.87 (2H, s) 6.74-6.85 (3H, m), 6.96-7.07 (3H,m), 7.17-7.34 (2H, m), 7.56 (2H, m), 7.89 (1H, s).

LC/MS [MH+]=478, RT=3.80 min.

Example 745-{2-[5-methyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(propionamido)benzoicAcid

The title compound was prepared from5-{2-[5-methyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(propionamido)benzoic acid 4-fluorobenzylester following the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 1.19-1.27 (3H, m) 2.03-2.07 (2H, m), 2.20 (3H, s),2.34-2.36 (2H, m), 2.84-2.91 (4H, m), 4.90 (2H, s) 6.78-7.22 (8H, m),7.47 (1H, s), 7.58 (1H, s), 7.98 (1H, s).

LC/MS [MH+]=474, RT=3.64 min.

Example 755-{2-[5-methyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(propionamido)benzoicAcid

The title compound was prepared from5-{2-[5-methyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(propionamido)benzoicacid 2,4-difluorobenzyl ester following the standard hydrolysisprocedure.

¹H NMR (d₆DMSO) δ: 1.04-1.10 (3H, m) 1.94-1.98 (2H, m), 2.14 (3H, s),2.25-2.30 (2H, m), 2.73-2.83 (4H, m), 4.97 (2H, s) 6.83 (1H, s),6.95-7.03 (3H, m), 7.22-7.26 (2H, m), 7.31 (1H, s), 7.61 (1H, s), 7.97(1H, s), 9.87 (1H, bs).

LC/MS [MH+]=492, RT=3.58 min.

Example 765-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-2-methylbenzoic Acid

Prepared according to the standard hydrolysis procedure using5-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-2-methylbenzoic acidethyl ester to give the product as a colourless solid 46 mg 43%

¹HNMR (CDCl₃) δ: 2.02-2.09 (2H, m), 2.57 (3H, s), 2.85 (2H, t, J=6 Hz),2.92 (2H, t, J=6 Hz), 4.88 (2H, s), 6.81 (1H,d, J=12 Hz), 6.98-7.30 (9H,m), 7.88 (1H, s).

LC/MS: Rt=4.03 min [M−H]417 (1 Cl)

Example 775-[2-(2-Benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-propionylaminobenzoicAcid

Prepared according to the standard hydrolysis procedure using5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-propionylaminobenzoicacid methyl ester to give the product as a yellow oil 35 mg 73%.

¹H NMR (CDCl₃) δ: 1.25 (3H, t, J=12 Hz), 2.02-2.08 (2H, m), 2.45 (2H, q,J=12Hz), 2.82-2.90 (4H, m), 4.96 (2H, s), 6.82 (1H, d, J=12 Hz), 7.02(1H, s), 7.12 (1H, d, J=12Hz), 7.14-7.36 (6H, m), 7.87 (1H,s), 8.50 (1H,d, J=12 Hz).

LC/MS: Rt=4.10 [M+H] 476 (1 Cl).

Example 782-{2-[5-Chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}isonicotinicAcid

Prepared according to the standard hydrolysis procedure using2-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}isonicotinicacid ethyl ester to give the product as a colourless solid 38 mg 54%.

¹HMR (DMSO-d₆) δ: 2.05-2.09 (2H, m), 2.87 (2H, t, J=6 Hz), 3.04 (2H, t,J=6 Hz), 4.92 (2H, s), 6.75-6.86 (3H, m), 7.06-7.18 (3H, m), 7.50-7.54(2H, m), 8.55 (1H, d, J=6 Hz).

LC/MS: Rt=3.67 [M+H] 442 (1 Cl).

Example 792-{2-[5-Chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}isonicotinicAcid

Prepared according to the standard hydrolysis procedure to give theproduct as a colourless solid 36 mg 71%.

¹HNMR (CDCl₃) δ: 2.05-2.07 (2H, m), 2.86 (2H, m), 3.03 (2H, m), 4.87(2H, s), 6.81-7.13 (6H, m), 7.40-7.52 (3H, m), 8.56 (1H, br s).

LC/MS: Rt=3.92 [M+H] 424 (1 Cl).

Example 80 2-{2-[5-Chloro-2-benzyloxyphenyl]clopent-1-enyl}isonicotinicAcid

Prepared according to the standard hydrolysis procedure to give theproduct as a colourless solid 20 mg 32%.

¹HNMR (CDCl₃) δ: 2.07-2.12 (2H, m), 2.92 (2H, t, J=6 Hz), 3.07 (2H, t,J=6 Hz), 4.94 (2H, s), 6.84 (1H, d, J=12 Hz), 7.07 (1H, s), 7.15-7.30(6H, m), 7.55-7.58 (2H, m), 8.65 (1H, d, J=12 Hz).

LC/MS: Rt=3.61 [M+H] 406 (1 Cl).

Example 812-{2-[5-Bromo-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}isonicotinicAcid

Prepared according to the standard hydrolysis procedure to give theproduct as a colourless solid 10 mg 25%.

¹H NMR (CDCl₃) δ: 2.05-2.10 (2H, m), 2.88 (2H, t, J=6 Hz), 3.04 (2H, t,J=6 Hz), 4.85 (2H, t), 6.75 (1H, d, J=12 Hz), 6.95 (2H, m), 7.11 (2H,m), 7.26-7.28 (3H, m), 7.53-7.55 (2H, m), 8.56 (1H, d, J=6 Hz).

LC/MS: Rt=3.70 [M+H] 468, 470 (1 Br).

Example 825-[2-(2-Benzyloxy-5-chlorophenyl)cyclopent-1-enyl]3-propionylaminobenzoicAcid

Prepared according to the standard hydrolysis procedure to give theproduct as a colourless solid 53 mg 53%.

¹H NMR (CDCl₃): δ: 1.19 (3H, t, J=12 Hz), 2.04-2.08 (2H, m), 2.34 (2H,q, J=12 Hz), 2.83-2.93 (4H, m), 4.96 (2H, s), 6.82 (1H, d, J=12 Hz),6.96-7.00 (2H, m), 7.12-7.32 (5H, m), 7.49 (1H, s), 7.55 (1H, s), 7.96(1H, s).

LC/MS: Rt=3.89 [M+H] 476 (1 Cl).

Example 835-[2-(2-Benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-3-isobutyrylaminobenzoicAcid

Prepared according to the standard hydrolysis procedure to give theproduct as a colourless solid 58 mg 66%.

¹H NMR (CDCl₃) δ: 1.17 (6H, d, J=12 Hz), 2.02-2.05 (2H, m), 2.55 (1H,m), 2.83-2.90 (4H, m), 4.98 (2H, s), 6.82 (1H, d, J=12 Hz), 6.96 (1H,s), 7.08 (1H, d, J=12 Hz), 7.22-7.33 (4H, m), 7.45 (1H, s), 7.80 (1H,s), 7.94 (1H, s), 9.09 (1H,s).

LC/MS: Rt=3.99 [M+H] 490 (1 Cl).

Example 845-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-pyrrolidin-1-yl)benzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃): δ: 2.01-2.13 (4H, m), 2.54 (2H, t, J=7.9 Hz), 2.89 (2H,t, J=7.6 Hz), 2.97 (2H, t, J=7.5 Hz), 3.42 (2H, t, J=7.0 Hz), 5.06 (2H,s), 6.97 (1H, d, J=8.6 Hz), 7.20-7.33 (6H, m), 7.44 (1H, d, J=8.6 Hz),7.48 (1H, s), 7.65 (1H, s), 8.12 (1H, s).

LC/MS [MH−]=520, 521 Rt=3.82.

Example 855-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-pyrrolidin-1-yl)benzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.02-2.12 (4H, m), 2.55 (2H, t, J=8.0 Hz), 2.87 (2H,t, J=7.4 Hz), 2.95 (2H, t, J=7.3 Hz), 3.50 (2H, t, J=7.0 Hz), 4.99 (2H,s), 6.94-7.01 (3H, m), 7.15-7.19 (2H, m), 7.34 (1H, s), 7.45 (1H, d,J=8.6 Hz), 7.56 (1H, s), 7.61 (1H, s), 8.05 (1H, s).

LC/MS[MH−]=538, 539 Rt=3.91.

Example 865-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-pyrrolidin-1-yl)benzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.04-2.09 (4H, m), 2.56 (2H, t, J=8.1 Hz), 2.84 (2H,t, J=7.3 Hz), 2.94 (2H, t, J=7.0 Hz), 3.53 (2H, t, J=7.0 Hz), 4.92 (2H,s), 6.82 (1H, d, J=8.7 Hz), 6.98 (2H, t, J=8.6 Hz), 7.04 (1H, s),7.13-7.19 (3H, m), 7.57 (1H, s), 7.63 (1H, s), 8.07 (1H, s).

LC/MS[MH−]=504, 506 Rt=3.91.

Example 875-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1enyl}-3-(2-oxo-piperidin-1-yl)benzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 1.80 (4H, bs), 2.06-2.10 (2H, m), 2.49 (2H, t, J=6.3Hz), 2.84-2.93 (4H, m), 3.21 (2H, bs), 4.97 (2H, s), 6.93-7.06 (4H, m),7.15-7.19 (2H, m), 7.33 (1H, s), 7.44 (1H, d, J=8.4 Hz), 7.71 (2H, s).

LC/MS[MH−]=552, 553 Rt=3.87

Example 885-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-piperidin-1-yl)benzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 1.76-1.83 (4H, m), 2.06-2.13 (2H, m), 2.49 (2H, t,J=6.6 Hz), 2.89 (2H, t, J=7.6 Hz), 2.94 (2H, t, J=7.4 Hz), 3.15 (2H, t,J=6.0 Hz), 5.05 (2H, s), 6.96 (1H, d, J=8.6 Hz), 7.04 (1H, s), 7.20-7.31(6H, m), 7.72 (1H, d, J=8.6 Hz), 7.74 (2H, d, J=10 Hz).

LC/MS[MH−]=534, 535 Rt=3.78.

Example 895-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-piperidin-1-yl)benzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 1.84 (2H, bs), 2.03-2.07 (2H, m), 2.51 (2H, t, J=6.2Hz), 2.84 (2H, t, J=7.3 Hz), 2.92 (2H, t, J=7.3 Hz), 3.27 (2H, t, J=5.9Hz), 4.89 (2H, s), 6.80 (1H, d, J=8.8 Hz), 6.97 (2H, t, J=8.7 Hz),7.04-7.17 (5H, m), 7.72 (2H, s).

LC/MS[MH−]=518, 520 Rt=3.87.

Example 906-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicAcid

Prepared using general procedure C(iii).

¹H NMR (CDCl₃) δ: 2.10-2.14 (2H, m), 2.98 (2H, t, J=7.5 Hz), 3.12 (2H,t, J=7.4 Hz), 5.02 (2H, s), 7.1545 (2H, d, J=7.6 Hz), 7.23-7.27 (4H, m),7.42 (1H, s), 7.58 (1H, d, J=5.2 Hz), 8.17 (1H, s), 8.83 (1H, s).

Example 916-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicAcid

Prepared using general procedure C(iii).

¹H NMR (CDCl₃) δ: 2.13-2.17 (2H, m), 2.95 (2H, t, J=7.5 Hz), 3.05 (2H,t, J=7.5 Hz), 4.87 (2H, s), 6.92 (1H, d, J=8.8 Hz), 7.06-7.35 (7H, m),8.53 (1H, s), 9.02 (1H, s).

LC/MS[MH+]=407, 409 Rt=4.16.

Example 926-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicAcid

Prepared using general procedure C(iii).

¹H NMR (CDCl₃) δ: 2.11-2.18 (2H, m), 2.92 (2H, t, J=7.1 Hz), 3.05 (2H,t, J=7.1 Hz), 4.85 (2H, s), 6.89-7.33 (7H, m), 8.54 (1H, s), 9.05 (1H,s).

LC/MS[MH+]=425, 427 Rt=3.76.

Example 935-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.02-2.08 (2H, m), 2.85-292 (4H, m), 5.03 (2H, s),6.55 (1H, s), 6.93 (1H, d, J=8.6 Hz), 7.15 (1H, s), 7.16-7.42 (8H, m).

LC/MS[MH−]=452 Rt=3.6

Example 946-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.02-2.09 (2H, m), 2.82-291 (4H, m), 4.96 (2H, s),6.55 (1H, s), 6.91 (1H, d, J=8.6 Hz), 6.99 (2H, t, J=8.6 Hz), 7.15-7.33(5H, m), 7.43 (1H, d, J=8.6 Hz).

LC/MS[MH−]=470 Rt=3.6.

Example 955-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoic Acid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.01-2.08 (2H, m), 2.83 (2H, t, J=7.4 Hz), 2.89 (2H,t, J=7.4 Hz), 4.96 (2H, s), 6.57 (1H, s), 6.81 (1H, d, J=8.7 Hz),7.01-7.31 (9H, m).

LC/MS[MH−]=418, 420 Rt=3.6.

Example 965-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 1.99-2.06 (2H, m), 2.79-2.87 (4H, m), 4.88 (2H, s),6.57 (1H, s), 6.78 (1H, d, J=8.7 Hz), 6.96-7.17 (8H, m).

LC/MS[MH−]=436, 438 Rt=3.6.

Example 975-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 1.99-2.05 (2H, m), 2.80 (2H, t, J=7.3 Hz), 2.88 (2H,t, J=7.3 Hz), 4.94 (2H, s), 6.56 (1H, s), 6.75-6.83 (3H, m), 7.04 (1H,s), 7.12-7.17 (4H, m).

LC/MS[MH−]=454, 456 Rt=3.6.

Example 985-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.03-2.10 (2H, m), 2.72 (3H, s), 2.83 (2H, t, J=7.3Hz), 2.92 (2H, t, J=7.3 Hz), 4.97 (2H, s), 6.70 (1H, s), 6.86(1H,s).(1H, d, J=8.8 Hz), 6.96-7.03 (3H, m), 7.13-7.25 (3H, m), 7.6 (1H,s), 7.72 (1H, s).

LC/MS[MH−]=514, 516 Rt=3.84.

Example 995-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoicAcid

Prepared according to the standard hydrolysis procedure.

¹HNMR (CDCl₃) δ: 2.08-2.12 (2H, m), 2.61 (3H, s), 2.88 (2H, t, J=7.6Hz), 2.94 (2H, t, J=7.6 Hz), 5.11 (2H, s), 6.49 (1H, bs), 7.01 (1H, d),7.13 (1H, s) 7.23-7.34 (6H, m), 7.45 (1H, d, J=8.7 Hz), 7.58 (1H, s),7.72 (1H, s).

LC/MS[MH−]=530 Rt=3.84.

Example 1005-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.06-2.10 (2H, m), 2.64 (3H, s), 2.84-2.95 (4H, r),5.05 (2H, s), 6.72 (1H, br s), 6.98-7.04 (3H, m), 7.12-7.26 (3H, m),7.46 (1H, d, J=8.6 Hz), 7.68 (1H, s), 7.70 (1H, s).

LC/MS[MH−]=548 Rt=3.93.

Example 1015-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3}-methanesulphonylaminoBenzoic Acid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.06-2.10 (2H, bm), 2.64 (3H, s), 2.83 (2H, bs), 2.91(2H, bs), 5.09 (2H, s), 6.79-6.86 (3H, m), 7.04 (1H, d, J=8.6 Hz), 7.17(1H, s), 7.23-7.26 (1H, m), 7.48 (1H, d, J=8.4 Hz), 7.56 (1H, s), 7.68(1H, s).

LC/MS[MH−]=566 Rt=3.7.

Example 1025-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-acetamidobenzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.04-2.11 (5H, m), 2.85-2.91 (4H, m), 4.97 (2H, s),6.92-7.56 (9H, m), 7.80 (1H, s).

LC/MS[MH−]=512, 513 Rt=3.6.

Example 1035-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl)-3-acetamidobenzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.02-2.1 (2H, bm), 2.13 (3H, s), 2.84 (2H, t, J=7.1),2.91 (2H, t, J=7.1 Hz), 5.03 (2H, s), 6.76-6.83 (2H, m), 6.97 (1H, d,J=8.6 Hz), 7.16-7.2 (1H, m), 7.31 (1H, s), 7.46 (1H, d, J=7.3 Hz), 7.51(1H, s), 7.59 (1H, s), 7.85 (1H, s).

LC/MS[MH−]=530, 531 Rt=3.6.

Example 1045-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-acetamidobenzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.04 (3H, s), 2.07-2.11 (2H, bm), 2.88-2.92 (4H, m),5.03 (2H, s), 6.95 (1H, d), 7.11 (1H, bs), 7.21-7.31 (5H, m), 7.43 (1H,d), 7.54 (2H, s), 7.85 (1H, s).

LC/MS[MH−]=494 Rt=3.78.

Example 1055-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-acetamidobenzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.01-2.09 (2H, m), 2.13 (3H, s), 2.82 (2H, t, J=7.1Hz), 2.91 (2H, t, J=7.1 Hz), 4.95 (2H, s), 6.76-7.18 (6H, m), 7.54 (2H,s), 7.86 (1H, s).

LC/MS[MH−]=496, 498 Rt=3.63.

Example 1065-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-acetamidobenzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.03-2.07 (2H, m), 2.13 (3H, s), 2.83 (2H, t, J=7.1Hz), 2.90 (2H, t, J=7.1 Hz), 4.89 (2H, s), 6.80 (1H, d, J=8.8 Hz),6.96-7.18 (6H, m), 7.53 (2H, d, J=13 Hz), 7.87 (1H, s).

LC/MS[MH−]=478, 480 Rt=3.78.

Example 1075-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopenten-1-enyl}-3-acetamidobenzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.03-2.10 (2H, m), 2.13 (3H, s), 2.85 (2H, t, J=7.2Hz), 2.89 (2H, t, J=7.2 Hz), 4.96 (2H,s), 6.82 (1H, d, J=8.8 Hz), 7.00(2H, s), 7.13 (1H, d, J=8.8 Hz), 7.21-7.32 (5H, m), 7.45 (1H, s), 7.58(1H, s), 7.93 (1H, s). LC/MS[MH−]=460, 462 Rt=3.59.

Example 1085-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(morpholin-4-yl)benzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.08-2.11 (2H, m), 2.77 (4H, t, J=4.8 Hz), 2.88 (2H,t, J=7.1), 2.96 (2H, t, J=7.1 Hz), 3.68 (4H, t, J=4.7 Hz), 5.04 (2H, s),6.75 (1H, s), 6.93 (1H, d, J=8.6 Hz), 7.19-7.46 (9H, m).

LC/MS [MH−]=522, 523 Rt=4.08.

Example 1095-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(morpholin-4-yl)benzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.06-2.11 (2H, m), 2.78 (4H, t, J=4.8 Hz), 2.85 (2H,t, J=7.1 Hz), 2.94 (2H, t, J=7.1 Hz), 3.69 (4H, t, J=4.7 Hz), 4.97 (2H,s), 6.73 (1H, s), 6.91 (1H, d, J=8.6 Hz), 6.97 (2H, t, J=8.6 Hz),7.11-7.14 (2H, m), 7.38 (2H, d, J=7.3 Hz), 7.43 (2H, bs).

LC/MS[MH−]=540, 541 Rt=4.11.

Example 1105-{2-[5-chloro-2-(-4-fluorobenzyloxy)phenyl]cyclopenten-1-enyl}-3-(morpholinyl)benzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.03-2.11 (2H, m), 2.82-2.86 (6H, m), 2.93 (2H, t,J=7.1 Hz), 3.73 (4H, t, J=4.7 Hz), 4.90 (2H, s), 6.80 (1H, s), 6.96 (2H,t, J=6.7 Hz), 7.0-7.18 (5H, m), 7.40 (1H, s), 7.45 (1H, s).

LC/MS[MH−]=506, 508 Rt=3.82.

Example 1115-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methylaminobenzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.01-2.08 (2H, m), 2.61 (3H, s), 2.82 (2H, t, J=7.4Hz), 2.91 (2H, t, J=7.4 Hz), 4.89 (2H, s), 6.50 (1H, s), 6.79 (1H, d,J=8.7 Hz), 6.98 (2H, t, J=8.7 Hz), 7.06-7.17 (6H, m).

LC/MS[MH−]=450, 452 Rt=3.80.

Example 1125-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methylaminobenzoicAcid

Prepared according to general procedure for ester deprotection.

¹H NMR (CDCl₃) δ: 2.05-2.10 (2H, m), 2.56 (3H, s), 2.85 (2H, t, J=7.4Hz), 2.93 (2H, t, J=7.4 Hz), 4.96 (2H, s), 6.45 (1H, s), 6.91 (1H, d,J=8.6 Hz), 6.98 (2H, t, J=8.7 Hz), 7.09 (1H, s), 7.13-7.16 (2H, m), 7.24(1H, s), 7.37 (1H, s), 7.43 (1H, d, J=8.6 Hz).

LC/MS[MH−]=484, 485 Rt=3.81

Example 1135-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-methylaminobenzoicAcid

Prepared according to the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.04-2.09 (2H, m), 2.55 (3H, s), 2.87 (2H, t, J=7.3Hz), 2.91 (2H, t, J=7.2 Hz), 5.03 (2H, s), 6.46 (1H, s), 6.93 (1H, d,J=8.7 Hz), 7.08 (1H, s), 7.19-7.35 (7H, m), 7.42 (1H, d, J=8.6 Hz).

Example 1142{2-[5-Trifluoromethyl-2-(2,4-diflurobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-4-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.07-2.14 (2H, m), 2.93 (2H, t, J=8 Hz), 3.08 (2H, t,J=7.5 Hz), 5.01 (2H, s), 6.76-6.82 (2H, m), 7.00 (1H, d, J=8.6 Hz),7.13-7.19 (1H, m), 7.38 (1H, s), 7.48 (2H, s), 7.57 (1H, d, J=6.5 Hz),8.62 (1H, d, J=4.7 Hz).

LC/MS: Rt 3.93, [MH−] 474.0, [MH+] 476.0

Example 1152{2-[5-bromo-2-(2,4-diflurobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-4-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.05-2.12 (2H, m), 2.89 (2H, t, J=8 Hz), 3.06 (2H, t,J=7 Hz), 4.93 (2H, s), 6.83-6.77 (3H, m), 7.12-7.18 (1H, m), 7.24 (1H,s), 7.33 (1H, d, J=8.8 Hz), 7.52 (1H, s), 7.57 (1H, d, J=5 Hz), 8.63(1H, d, J=5 Hz).

LC/MS: Rt 3.99, [MH+] 487.9, [MH−] 485.9.

Example 1162{2-[5-bromo-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-4-carboxylicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.05-2.13 (2H, m), 2.92 (2H, t, J=7.2 Hz), 3.07 (2H,t, J=7.4 Hz), 4.95 (2H, s), 6.80 (1H, d, J=8.8 Hz), 7.17-7.32 (7H, m),7.54 (1H, s), 7.58 (1H, d, J=5.1 Hz) 8.66 (1H, d, J=5 Hz).

LC/MS: Rt 3.95, [MH+] 451.9, [MH−] 449.9.

Example 1172-{2-[5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-5-amino-6-carboxylicAcid

Prepared by general procedure B(iii) but using2-[5-trifluoromethyl-2-(2,4-diflurobenzyloxy)phenyl]boronic acid insteadof (5-chloro-2-benzyloxyphenyl)-boronic acid and3-amino-6-(2-bromocyclopent-1-enyl)pyrazine-2-carboxylic acid ethylester instead of 3-(2-bromocyclopent-1-enyl)-6-methylbenzoic acid ethylester.

¹H NMR (CDCl₃) δ: 2.08-2.15 (2H, m), 2.88 (2H, t, J=7.5 Hz), 2.97 (2H,t, J=7.6 Hz), 5.02 (2H, s), 6.78-6.82 (2H, m), 7.08-7.18 (2H, m), 7.41(1H, s), 7.57 (1H, d, J=8.6 Hz), 8.03 (1H, s), 9.80-10.09 (1H, br s).

LC/MS: Rt 3.73, [MH+] 492.0, [MH−] 490.0.

Example 1182-{2-[5-Chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-aminopyrazine-6-carboxylicAcid

Prepared by general procedure B(iii) but using3-amino-6-(2-bromocyclopent-1-enyl}-pyrazine-2-carboxylic acid ethylester instead of 3-(2-bromocyclopent-1-enyl)-6-methylbenzoic acid ethylester.

¹H NMR (CDCl₃) δ: 2.08-2.14 (2H, m), 2.89 (2H, t, J=7.4 Hz), 2.96 (2H,t, J=7.5 Hz), 4.93 (2H, s), 6.91 (1H, d, J=8.8 Hz), 7.13-7.15 (3H, m),7.22 (1H, d, J=8.7 Hz), 7.28-7.30 (3H, m), 8.05 (1H, s), 9.85-10.20 (1H,br s).

LC/MS: Rt 3.72, [MH+] 422.0, [MH−] 420.0.

Example 1193-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.05-2.12 (2H, m), 2.18 (3H, s), 2.87-2.96 (4H, m),5.03 (2H, s), 6.94 (1H, d, J=8.6 Hz), 7.06 (1H, s), 7.20-7.33 (6H, m),7.44 (1H, d, J=8.6 Hz), 7.65 (2H, s).

LC/MS: Rt 3.99, [MH−] 451.3.

Example 1203-{2-[5-Chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.03-2.11 (2H, m), 2.21 (3H, s), 2.84-2.94 (4H, m),4.95 (2H, m), 6.81 (1H, d, J=8.8 Hz), 7.02 (1H, s), 7.09 (1H, s), 7.13(1H, d, J=8.7 Hz), 7.19-7.33 (5H, m), 7.66-7.68 (2H, m).

LC/MS: Rt 4.23, [MS−] 417.1.

Example 1216-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicAcid

Prepared using the standard hydrolysis procedure.

¹HNMR (CDCl₃): 2.10-2.17 (2H, m), 2.91 (2H,t,J=7.1), 3.05 (2H,t,J=7.1),4.90 (2H,s), 6.72-6.80 (2H, m), 6.95 (1H,d,J=8.8), 7.06-7.12 (2H,m),7.26-7.29 (1H,m), 8.52 (1H,s), 9.06 (1H,s).

LC/MS[MH+]=443, 445 Rt=3.80.

Example 1225-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(morpholin-4-yl)benzoicAcid

Prepared using the standard hydrolysis procedure.

¹HNMR (CDCl3): 2.04-2.10 (2H,m), 2.79 (4H,t,J=4.8), 2.84 (2H,t,J=7.1),2.94 (2H,t,J=7.1), 3.70 (4H,t,J=4.7), 5.02 (2H,s), 6.72 (1H,s),6.76-6.81 (2H,m), 6.96 (1H,d,J=8.6), 7.07-7.10 (1H,m), 7.39(3H,d,J=10.6), 7.46 (1H,d,J=8.6).

LC/MS[MH−]=558, 559 Rt=4.05.

Example 123 5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopenten-1-enyl}-3-morpholin-4-ylbenzoic Acid

Prepared using the standard hydrolysis procedure.

¹H NMR (CDCl₃): 2.06-2.09 (2H,m), 2.82-2.87 (6H,m), 2.94 (2H,t,J=7.1),3.72 (4H,t,J=4.7), 4.97 (2H,s), 6.80-6.82 (2H,m), 7.04 (1H,s), 7.10(1H,dd,J=2.6, J=8.7), 7.19-7.31 (5H,m), 7.41 (1H,s), 7.48 (1H,s).

LC/MS[MH-3=488, 490 Rt=3.80.

Example 1245-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopenten-1-enyl}-3-(morpholin-4-yl)benzoicAcid

Prepared using the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.04-2.08 (2H, m), 2.80-2.86 (6H, m), 2.92 (2H, t,J=7.1 Hz), 3.73 (4H, t, J=4.7 Hz), 4.95 (2H, s), 6.76-6.85 (4H, m),7.06-7.16 (3H, m), 7.38 (1H, s), 7.41 (1H, s).

LC/MS[MH−]=524, 526 Rt=4.06.

Example 1255-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoicAcid

Prepared using the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.03-2.10 (2H,m), 2.73 (3H,s), 2.81 (2H,t,J=7 Hz),2.91 (2H,t,J=7 Hz), 5.02 (2H, s), 6.70 (1H, bs), 6.78-6.96 (4H,m),7.16-7.26 (3H,m), 7.6 (1H,s), 7.70 (1H,s).

LC/MS[MH−]=532, 534 Rt=3.68.

Example 1265-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminoBenzoic Acid

Prepared using the standard hydrolysis procedure.

¹H NMR (CDCl₃): δ: 2.06-2.10 (2H,m), 2.67 (3H,s), 2.86 (2H,t,J=7 Hz),2.92 (2H,t,J=7 Hz), 5.03 (2H, s), 6.50 (1H, bs), 6.87 (1H,d,J=9 Hz),6.94 (1H,s), 7.13-7.15 (2H,m), 7.26-7.34 (5H,m), 7.61 (1H,s), 7.74(1H,s).

LC/MS[MH−]=496, 498 Rt=3.64.

Example 1275-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-diethylaminobenzoicAcid

Prepared using the standard hydrolysis procedure.

¹HNMR (CDCl₃): 0.86 (6H, t, J=7 Hz), 2.04-2.09 (2H, m), 2.86 (2H, t, J=7Hz), 2.96 (2H, t, J=7 Hz), 3.04 (4H, q, J=7 Hz), 5.03 (2H,s), 6.53(1H,s), 6.93 (1H,d,J=8 Hz), 7.17-7.42 (9H, m).

LC/MS[MH−]=508, 509 Rt=4.29.

Example 1286-{2-[5-Methyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicAcid

Prepared by the standard hydrolysis procedure using 6-{2-[5-methyl-2-(4fluorobenzyloxy)phenyl]cyclopent-1-enyl}-pyrazine-2-carboxylic acidethyl ester.

¹H NMR (CDCl₃) δ: 2.12-2.16 (2H, m), 2.27 (3H, s), 2.93-2.97 (2H, m).3.02-3.06 (2H, m), 4.86 (2H, s), 6.88 (1H, d, J=8 Hz), 6.92-6.97 (3H,m), 7.08-7.12 (3H, m), 8.55 (1H, s), 9.02 (1H, s).

LC/MS: Rt 4.04, [MH+] 405.2.

Example 1296-{2-[5-Methyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicAcid

Prepared by the standard hydrolysis procedure using6-{2-[5-methyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicacid ethyl ester.

¹H NMR (CDCl₃) δ: 2.10-2.17 (2H, m), 2.27 (3H, s), 2.91-2.95 (2H, m).3.01-3.05 (2H, m), 4.91 (2H, s), 6.71-6.78 (2H, m), 6.92-6.94 (2H, m),7.09-7.14 (2H, m), 8.54 (1H, s), 9.04 (1H, s).

LC/MS: Rt 3.77, [MH+] 423.4.

Example 1306-{2-[5-Fluoro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared by the standard hydrolysis procedure using6-{2-[5-fluoro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid benzyl ester.

¹H NMR (CDCl₃) δ: 2.09-2.17 (2H, m), 2.90-2.94 (2H, m). 3.01-3.05 (2H,m), 4.91 (2H, s), 6.83 (1H, dd, J=9 Hz, 3 Hz), 6.92-6.97 (2H, m),7.12-7.14 (2H, m), 7.25-7.29 (4H, m), 7.69 (1H, t, J=8 Hz), 7.89 (1H, d,J=8 Hz).

LC/MS: Rt 3.33, [MH+] 390.4.

Example 1316-{2-[5-Fluoro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Was prepared by the standard hydrolysis procedure using6-{2-[5-fluoro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid 4-fluorobenzyl ester.

¹H NMR (CDCl₃) δ: 2.08-2.16 (2H, m), 2.88-2.92 (2H, m). 3.00-3.04 (2H,m), 4.86 (2H, s), 6.82 (1H, dd, J=9 Hz, 3 Hz), 6.84-6.98 (4H, m),7.08-7.12 (2H, m), 7.28 (1H, d, J=8 Hz), 7.71 (1H, t, J=8 Hz), 7.90 (1H,d, J=8 Hz).

LC/MS: Rt 3.36, [MH+] 408.4.

Example 1326-{2-[5-Fluoro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-pyridine-2-carboxylicAcid

Prepared by the standard hydrolysis procedure using6-{2-[5-fluoro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid 2,4-difluorobenzyl ester.

¹H NMR (CDCl₃) δ: 2.08-2.15 (2H, m), 2.87-2.91 (2H, m). 3.00-3.03 (2H,m), 4.91 (2H, s), 6.72-6.77 (2H, m), 6.83 (1H, dd, J=9 Hz, 3 Hz),6.95-7.00 (2H, m), 7.10 (1H, q, J=8 Hz), 7.28 (1H, d, J=8 Hz), 7.71 (1H,t, J=8 Hz), 7.91 (1H, d, J=8 Hz).

LC/MS: Rt 3.41, [MH+] 426.3.

Example 1336-{2-[5-Chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-pyridazine-4-carboxylicAcid

Prepared by the standard hydrolysis procedure using6-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridazine-4-carboxylicacid ethyl ester.

¹H NMR (DMSO-d₈) δ: 2.03-2.10 (2H, m), 2.89-2.93 (2H, m). 3.09-3.13 (2H,m), 4.96 (2H, s), 7.07-7.09 (2H, m), 7.14 (1H, d, J=9 Hz), 7.23-7.26(4H, m), 7.35 (1H, dd, J=9 Hz, 2 Hz), 7.47 (1H, s), 9.27 (1H, s), 13.9(1H, br s).

LC/MS: Rt 3.79, [MH+] 407.3, 409.3.

Example 1346-{2-[5-Chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridazine-4-carboxylicAcid

Prepared by the standard hydrolysis procedure using6-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridazine-4-carboxylicacid ethyl ester.

¹H NMR (DMSO-d₈) δ: 2.03-2.09 (2H, m), 2.89-2.92 (2H, m). 3.08-3.12 (2H,m), 4.93 (2H, s), 7.06-7.15 (5H, m), 7.24 (1H, d, J=3 Hz), 7.36 (1H, dd,J=9 Hz, 3 Hz), 7.43 (1H, d, J=2 Hz), 9.26 (1H, s), 13.8 (1H, br s).

LC/MS: Rt 3.82, [MH+] 425.3, 427.3.

Example 1356-{2-[5-Chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridazine-4-carboxylicAcid

Prepared by the standard hydrolysis procedure using6-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridazine-4-carboxylicacid ethyl ester.

¹H NMR (DMSO-d₆) δ: 1.99-2.06 (2H, m), 2.85-2.88 (2H, m). 3.05-3.09 (2H,m), 4.95 (2H, s), 6.98 (1H, dt, J=8 Hz, 2 Hz), 7.15 (1H, dt, J=8 Hz, 2Hz), 7.21-7.24 (3H, m), 7.37-7.40 (2H, m), 9.24 (1H, d, J=2 Hz), 13.8(1H, br s).

LC/MS: Rt 3.85, [MH+] 443.3, 445.3.

Example 1365-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-2-methylbenzoicAcid

Trifluoroacetic acid (1 ml) was added to a solution of5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-2-methylbenzoicacid (40 mg 0.08 mmol) in dichloromethane (5 ml). The reaction mixturewas stirred at room temperature for three hours. The solvent wasevaporated, and the residue chromatographed (RP silica C18,acetonitrile/water 30:70-100:0) to give the title compound as acolourless solid 24 mg 67%.

¹HMR (CDCl₃): 2.00-2.09 (2H,m), 2.56 (3H,s), 2.82 (2H,t,J=6 Hz), 2.9(2H,t,J=6 Hz), 4.93 (2H,s), 6.75-7.17 (7H,m), 7.25 (1H,s), 7.83 (1H,s).

LC/MS: Rt=4.25 [M−H] 453 (1 Cl).

Example 1375-[2-(2-(4-fluorobenzyloxy)-5-chlorophenyl)cyclopent-1-enyl]-2-methylbenzoicAcid

Trifluoroacetic acid (1 ml) was added to a solution of5-[2-(2-(4-fluorobenzyloxy)-5-chlorophenyl)cyclopent-1-enyl]-2-methylbenzoicacid t-butyl ester (60 mg 0.12 mmol) in dichloromethane (5 ml). Thereaction mixture was stirred at room temperature for three hours. Thesolvent was evaporated, and the residue chromatographed (RP silica C18,acetonitrile/water 30:70-100:0) to give the title compound as acolourless solid 17 mg 33%.

¹H NMR (CDCl₃): 2.01 (2H,m), 2.56 (3H,s), 2.83 (2H,t,J=6 Hz), 2.91(2H,t,J=6 Hz), 4.89(2 H,s) 6.80 (1H,d,J=8 Hz), 6.95-7.15 (8H,m), 7.84(1H,s).

LC/MS: Rt=4.22 [M−H] 435 (1 Cl).

Example 1385-[2-(2-(4-fluorobenzyloxy)-5-chlorophenyl)cyclopent-1-enyl]-2-fluorobenzoicAcid

Prepared according to the standard hydrolysis procedure using5-[2-(2-(4-fluorobenzyloxy)-5-chlorophenyl)cyclopent-1-enyl]-2-fluorobenzoicacid ethyl ester.

¹HMR (CDCl₃): 2.01-2.09 (2H,m), 2.83 (2H,t,J=6 Hz), 2.89 (2H,t,J=6 Hz),4.88 (2H,s), 6.80-7.19 (9H,m), 7.75 (1H,d,J=8 Hz).

Example 1395-[2-(2-benzyloxy)-5-chlorophenyl)cyclopent-1-enyl]-2-fluorobenzoic Acid

Prepared according to the standard hydrolysis procedure using5-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-2-fluorobenzoic acidethyl ester.

¹H NMR (CDCl₃): δ: 2.01-2.08 (2H, m), 2.78-2.91 (4H, m), 4.95 (2H, s),6.82-7.33 (10H, m), 7.78 (1H, d, J=8 Hz).

Example 1405-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}nicotinicAcid

Prepared by the standard hydrolysis procedure.

Product (18 mg, 90%)

LC/MS [MH+] 440 Rt=3.92 min.

¹H NMR (400 MHz, CDCl₃) δ: 2.32-2.14 (2H,m), 2.85-2.96 (4H, m) 4.98 (2H,s), 6.93-6.98 (1H, d, J=8 Hz), 7.14-7.20 (2H, m), 7.24-7.33 (4H, m),7.42-7.47 (1H, d, J=8 Hz), 8.30 (1H, s), 8.39 (1H,s), 8.96 (1H, s).

Example 141 4-{2-[2-(Benzyloxy)phenyl]cyclopent-1-enyl}benzoic Acid

Prepared by the standard hydrolysis procedure.

LC/MS [MH⁺] 371 Rt 3.72 min.

¹H NMR (400 MHz, CDCl₃) δ: 2.03-2.13 (2H, m), 2.87-2.97 (4H, m), 4.99(2H, s), 6.86 (1H, t, J=8 Hz), 6.93 (1H, d, J=8 Hz), 7.10 (1H, d, J=7Hz), 7.14-7.35 (8H, m), 7.84 (2H, d, J=8 Hz).

Example 142 4-{2-[5-Chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}benzoicAcid

Was prepared by the standard hydrolysis procedure.

¹H NMR (400 MHz, CDCl₃) δ: 2.02-2.12 (2H, m), 2.83-2.96 (4H, m), 4.93(2H, s), 6.82 (1H, d, J=9 Hz), 7.02 (1H, d, J=3 Hz), 7.12-7.20 (5H, m),7.24-7.33 (3H, m), 7.86 (2H, d, J=8 Hz).

LC/MS [MH⁻] 403 Rt=4.01 min.

Example 1433-{2-[5-Chloro-3-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.04-2.10 (2H, m), 2.22 (3H, s), 2.82-2.93 (4H, m),4.88 (2H, s), 6.80 (1H, d, J=8.8), 6.96-7.16 (7H, m), 7.66 (2H, m).

LC/MS: Rt 4.03, [MH−] 436.5.

Example 1443-{2-[5-Chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.02-2.10 (2H, m), 2.21 (3H, s), 2.81-2.93 (4H, m),4.93 (2H, s), 6.77-6.85 (3H, m), 7.03-7.18 (4H, m), 7.64 (2H, m).

LC/MS: Rt 4.05, [MH−] 453.3.

Example 1453-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.05-2.11 (2H, m), 2.19 (3H, s), 2.85-2.95 (4H, m),4.97 (2H, s), 6.92-7.05 (4H, m), 7.14-7.18 (2H, m), 7.32 (1H, s), 7.45(1H, m), 7.64 (2H, m).

LC/MS: Rt 4.00, [MH−] 469.3.

Example 1463-{2-[5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.04-2.12 (2H, m), 2.28-2.95 (4H, m), 5.02 (2H, s),6.78-6.83 (2H, m), 6.96-6.98 (1H, m), 7.04 (1H, s), 7.10-7.18 (1H, m),7.32 (1H, s), 7.46-7.49 (1H, m), 7.61 (1H, s), 7.65 (1H, s).

LC/MS: Rt 4.02, [MH−] 487.3.

Example 1473-{2-[5-Chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.05-2.12 (2H, m), 2.84-2.94 (4H, m), 4.96 (2H, s),6.84-6.86 (1H, m), 6.95-6.98 (1H, m), 7.02 (1H, s), 7.15-7.20 (3H, m),7.21-7.34 (3H, m), 7.50-7.52 (1H, m), 7.66 (1H, s).

LC/MS: Rt 4.05 [MH−] 421.3

Example 1483-{2-[5-Chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.03-2.11 (2H, m), 2.83-2.93 (4H, m), 4.89 (2H, s),6.82-6.84 (1H, m), 6.95-7.08 (4H, m), 7.14-7.20 (3H, m), 7.50-7.52 (1H,m), 7.64 (1H, s).

LC/MS: Rt 4.03 [MH−] 439.2.

Example 1493-{2-[5-Chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.03-2.11 (2H, m), 2.81-2.93 (4H, m), 4.94 (2H, s),6.78-6.95 (4H, m), 7.04 (1H, s), 7.12-7.20 (2H, m), 7.50-7.52 (1H, m),7.62 (1H, s).

LC/MS:

[MH−] 457.2.

Example 1503-{2-[5-Trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.05-2.13 (2H, m), 2.86-2.94 (4H, m), 4.97 (2H, s),6.91-7.03 (4H, m), 7.15-7.19 (2H, m), 7.33 (1H, s), 7.48-7.52 (2H, m),7.60 (1H, s).

LC/MS: Rt 3.98 [MH−] 473.3.

Example 1522-{2-[2-(4-fluorobenzyloxy)phenyl]-cyclopent-1-enyl}-isonicotinic Acid

isolated from the reaction mixture by filtration during preparation ofExample 81.

Yield 10 mg 25%.

¹H NMR (CDCl₃): 2.06-2.10 (2H,m), 2.93 (2H, br t), 3.05 (2H, br t), 4.93(2H,s), 6.88-7.23 (8H,m), 7.52-7.55 (2H,m), 8.66 (1H,d,J=6 Hz).

Example 1536-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared using the standard hydrolysis procedure.

¹H NMR (CDCl₃): 2.10-2.14 (2H, m), 2.91 (2H, t, J=7.4 Hz), 3.04 (2H, t,J=7.4 Hz), 4.92 (2H, s), 6.90 (1H, d, J=8.8 Hz), 7.09-7.12 (3H, m),7.21-7.29 (5H, m), 7.68 (1H, t, J=7.8 Hz), 7.91 (1H,d, J=7.6 Hz).

LC/MS[MH+]=406, 408 Rt=3.83

Example 1546-{2-[5-chloro-2-(4-bromobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Sodium Salt

Prepared using the standard hydrolysis procedure, but after dilutionwith water the solid was filtered, washed with water and dried in vacuo.

¹H NMR (DMSO-d₆): 1.92-1.98 (2H, m), 2.77-2.83 (2H, m), 2.82-2.89 (2H,m), 5.03 (2H, s), 6.63 (1H, d), 7.0 (1H, s), 7.06 (1H, d), 7.14 (2H, d,J=8.3 Hz), 7.23 (1H, d), 7.34 (1H, t), 7.50-7.54 (3H, m).

LC/MS [MH+]=486, 488 Rt=4.08.

Example 1556-{2-[5-chloro-2-(2-chloro-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared using the standard hydrolysis procedure.

¹H NMR (CDCl₃): 2.10-2.17 (2H, m), 2.90 (2H, t, J=7.4 Hz), 3.03 (2H, t,J=7.4 Hz), 4.95 (2H, s), 6.86 (1H, t, J=8.4), 6.92 (1H, d, J=8.8 Hz),7.06 (1H, d, J=8.4 Hz), 7.11-7.13 (2H, m), 7.24-7.30 (2H, m), 7.71 (1H,t, J=7.8 Hz), 7.90 (1H, d, J=7.6 Hz).

LC/MS[MH+]=458, 461 (2Cl) Rt=4.06.

Example 1566-{2-[5-chloro-2-(2,4,6-trifluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared using the standard hydrolysis procedure.

¹H NMR (CDCl₃): 2.02-2.09 (2H, m), 2.82 (2H, t, J=7.4 Hz), 2.96 (2H, t,J=7.4 Hz), 4.94 (2H, s), 6.86 (2H, t, J=8.4 Hz), 7.02-7.07 (2H, m),7.22-7.28 (2H, m), 7.71 (1H, t, J=7.8 Hz), 7.90 (1H, d, J=7.6 Hz).

LC/MS[MH+]=460, 462 Rt=3.84.

Example 1576-{2-[5-chloro-2-(2,6-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared using the standard hydrolysis procedure.

¹H NMR (CDCl₃): 2.02-2.09 (2H, m), 2.82 (2H, t, J=7.4 Hz), 2.95 (2H, t,J=7.4 Hz), 4.98 (2H, s), 6.77 (2H, t, J=7.9 Hz), 7.04-7.07 (2H, m),7.20-7.28(3H, m), 7.66 (1H, t, J=7.8 Hz), 7.87 (1H, d, J=7.5 Hz).

LC/MS[MH+]=442, 444 Rt=3.79.

Example 1586-{2-[5-chloro-2-(2-fluoro-4-trifluoromethylbenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared using the standard hydrolysis procedure.

¹H NMR (CDCl₃): 2.10-2.17 (2H, m), 2.90 (2H, t, J=7.4 Hz), 3.04 (2H, t,J=7.4 Hz), 5.02 (2H, s), 6.94 (1H, d, J=8.8 Hz), 7.12 (1H, s),7.26-7.32(5H, m), 7.71 (1H, t, J=7.8 Hz), 7.92 (1H, d, J=7.6 Hz).

LC/MS[MH+]=492, 494 Rt=4.07.

Example 1596-{2-[5-chloro-2-(3,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared using the standard hydrolysis procedure.

¹H NMR (CDCl₃): 2.09-2.16 (2H, m), 2.89 (2H, t, J=7.4 Hz), 3.04 (2H, t,J=7.4 Hz), 4.85 (2H,s), 6.85-6.91(3H, m), 7.01-7.11 (2H, m), 7.22-7.30(2H, m), 7.71 (1H, br t, J=7.1 Hz), 7.90 (1H, d, J=7.5 Hz).

LC/MS[MH+]=442, 444 Rt=3.90

Example 1606-{2-[5-chloro-2-(2,3-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Sodium Salt

Prepared using the standard hydrolysis procedure, but after dilutionwith water the solid was filtered, washed with water and dried in vacuo.

¹H NMR (DMSO-d₆): 1.90-1.97 (2H, m), 2.75-2.79 (2H, m), 2.92-2.95 (2H,m), 5.19 (2H, s), 6.60 (1H, d, J=7.8 Hz), 6.95 (1H, s), 7.07-7.58 (7H,m).

LC/MS[MH+]=442, 444 Rt=3.88.

Example 1616-{2-[5-chloro-2-(4-methylbenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid Sodium Salt

Prepared using the standard hydrolysis procedure, but after dilutionwith water the solid was filtered, washed with water and dried in vacuo.

¹H NMR (DMSO-d₆): 1.92-1.98 (2H, m), 2.27 (3H, s), 2.79-2.97 (4H, m),5.04 (2H, s), 6.61 (1H, d), 6.93 (1H, s), 7.08-7.14(5H, m), 7.25 (1H,d), 7.35 (1H, t), 7.53 (1H, d).

LC/MS[MH−]=418, 420 Rt=3.96.

Example 1626-{2-[5-chloro-2-(4-trifluoromethylbenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicAcid

Prepared using the standard hydrolysis procedure.

¹H NMR (CDCl₃): 2.04-2.17 (2H, m), 2.89 (2H, br s), 3.04 (2H, t, J=7.4Hz), 4.97 (2H, s), 6.87 (1H,d, J=8.7 Hz), 7.09 (1H, s), 7.22-7.27(4H,m), 7.52 (2H, d, J=8.1 Hz), 7.68 (1H, br s), 7.88 (1H, br s).

LC/MS[MH+]=474, 476 Rt=4.04.

Example 1633-{2[5-Trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-aminobenzoicAcid

Prepared by the standard hydrolysis procedure using3-{2[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-aminobenzoicmethyl ester.

¹H NMR (CDCl₃) δ: 2.02-2.10 (2H, m), 2.82-2.86 (2H, m), 2.88-2.92 (2H,m), 5.02 (2H, s), 6.54 (1H, d, J=2 Hz), 6.78-6.83 (2H, m), 6.96 (1H, d,9 Hz), 7.14-7.18 (2H, m), 7.23 (1H, s), 7.34 (1H, d, J=2 Hz), 7.46 (1H,dd, J=9 Hz, 2 Hz).

LC/MS: Rt 3.84, [MH+] 490.

Example 1642-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4-carboxylicAcid

Prepared by the standard hydrolysis procedure using2-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (DMSO-d₆) δ: 1.98-2.06 (2H, m), 2.91-2.95 (2H, m), 3.02-3.06 (2H,m), 5.02 (2H, s), 7.09-7.11 (2H, m), 7.18 (1H, d, J=9 Hz), 7.26-7.30(3H, m), 7.45 (1H, d, J=2 Hz), 7.56-7.622 H, m), 8.74 (1H, d, J=5 Hz),13.4 (1H, br s).

LC/MS: Rt 3.73, [MH+] 441.4.

Example 1655-{2-[5-Methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-2-acetamidobenzoicAcid

Prepared by the standard hydrolysis procedure using5-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-2-acetamidobenzoicacid ethyl ester

¹H NMR (CDCl₃) δ: 2.02-2.09 (2H, m), 2.20 (3H, s), 2.21 (3H, s)2.85-2.93 (4H, m), 4.96 (2H, s), 6.81 (1H, d, J=8 Hz), 6.86 (1H, d, J=2Hz), 6.99 (1H, dd, J=8 Hz, 2 Hz), 7.22-7.32 (6H, m), 7.92 (1H, d, J=2Hz), 8.42 (1H, d, J=9 Hz), 10.8 (1H, s).

LC/MS: Rt 3.91, [MH+] 442.4.

Example 1663-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-fluorobenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.06-2.13 (2H, m), 2.87-2.94 (4H, m), 5.03 (2H, s),6.88 (1H, dd, J=9 Hz, 3 Hz), 6.98 (1H, d, J=9 Hz), 7.18-7.33 (7H, m),7.46 (1H, d, J=9 Hz), 7.76 (1H, d, J=9 Hz).

LC/MS: Rt 3.88 [MH−] 455.

Example 1675-{2-[5-Trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-2-methylbenzoicAcid

Prepared by the standard hydrolysis procedure.

¹H NMR (CDCl₃) δ: 2.05-2.12 (2H, m), 2.56 (3H, s), 2.86-2.96 (4H, m),5.03 (2H, s), 6.95 (1H, d, J=9 Hz,), 6.98 (1H, d, J=8 Hz), 7.07 (1H, d,J=2 Hz), 7.19 (2H, d, J=2 Hz), 7.26-7.33 (4H, m), 7.43 (1H, d, J=2 Hz),7.85 (1H, s).

LC/MS: Rt 3.97 [MH−] 451.

Example 1685-{2-[5-chloro-2-(2,4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopyrrolidin-1-yl)benzoicAcid

Prepared according to general ester deprotection.

¹H NMR (CDCl₃) δ: 2.02-2.12 (4H, m), 2.56 (2H, t, J=8.1 Hz), 2.82 (2H,t, J=7.3 Hz), 2.94 (2H, t, J=7.0 Hz), 3.55 (2H, t, J=7.0 Hz), 4.97 (2H,s), 6.75-6.81 (2H, m), 6.80 (1H, d, J=8.1 Hz), 7.04 (1H, s), 7.14-7.18(2H, m), 7.57 (1H, s), 7.62 (1H, s), 8.05 (1H, s).

LC/MS[MH+]=524, 526 Rt=3.94.

Example 1695-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopyrrolidin-1-yl)benzoicAcid

Prepared according to general ester deprotection.

¹H NMR (CDCl₃) δ: 2.0-2.09 (4H, m), 2.54 (2H, t, J=8.1 Hz), 2.86(2 H, t,J=7.3 Hz), 2.95 (2H, t, J=7.0 Hz), 3.45 (2H, t, J=7.0 Hz), 4.99 (2H, s),6.84 (1H, d, J=8.8 Hz), 7.02 (1 H, s) 7.13(1H, d J=8.7 Hz), 7.20-7.31(5H, m), 7.49 (1H, s), 7.66 (1H, s), 8.15 (1H, s).

LC/MS[MH−]=486, 488 Rt=3.91.

Example 1705-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopyrrolidin-1-yl)benzoicAcid

¹H NMR (CDCl₃) δ: 2.04-2.10 (4H, m), 2.54 (2H, t, J=8.1 Hz), 2.85 (2H,t, J=7.3 Hz), 2.95 (2H, t, J=7.0 Hz), 3.51 (2H, t, J=7.0 Hz), 5.05 (2H,s), 6.77-6.82 (2H, m), 7.01 (1H, t, J=8.7 Hz), 7.14-7.16 (1H, m), 7.34(1H, s), 7.48 (1H, d, J=8.9 Hz), 7.57 (2H, d, J=10 Hz), 8.03 (1H, s).

LC/MS[MH−]=556 Rt=3.94.

Example 1715-{2-[5-chloro-2-(2,4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopiperidin-1-yl)benzoicAcid

Prepared according to general procedure for ester deprotection.

¹H NMR (CDCl₃) δ: 1.84(4H, bs), 2.04-2.10 (2H, m), 2.50 (2H, t, J=6.3Hz), 2.82 (2H, t, J=7.5 Hz), 2.91 (2H, t, J=7.3 Hz), 3.29 (2H, bs), 4.95(2H, s), 6.74-6.76 (3H, m), 7.04 (2H, bs), 7.12-7.17 (2H, m), 7.71 (2H,s).

LC/MS[MH−]=536, 538 Rt=3.91.

Example 1725-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopiperidin-1-yl)benzoicAcid

Prepared according to general procedure for ester deprotection.

¹H NMR (CDCl₃) δ: 1.79-1.84(4H, m), 2.04-2.10 (2H, m), 2.50 (2H, t,J=6.3 Hz), 2.86 (2H, t, J=7.5 Hz), 2.93 (2H, t, J=7.3 Hz), 3.22 (2H, t,J=6.0 Hz), 4.97 (2H, s), 6.82 (1H, d, J=8.8 Hz), 7.03 (2H, d, J=11 Hz),7.11 (2H, d, J=8.7 Hz), 7.19-7.31 (5H, m), 7.74 (1H, d, J=6 Hz).

LC/MS[MH+]=502, 504 Rt=3.87.

Example 1735-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopiperidin-1-yl)benzoicAcid

Prepared according to general procedure for ester deprotection.

¹H NMR (CDCl₃) δ: 1.80-1.84 (4H, m), 2.03-2.09 (2H, m), 2.48 (2H, t,J=6.3 Hz), 2.85 (2H, t, J=7.5 Hz), 2.93 (2H, t, J=7.3 Hz), 3.23 (2H, t,J=6.0 Hz), 5.04 (2H, s), 6.77-6.83 (2H, m), 6.98-7.02 (2H, m), 7.15-7.16(1H, m), 7.33 (1H, s), 7.47 (1H, d, J=8.4 Hz), 7.71 (2H, s).

LC/MS[MH−]=570, 571 Rt=3.91.

It is to be understood that the present invention covers allcombinations of particular and preferred subgroups described hereinabove.

Assays for Determining Biological Activity

The compounds of formula (I) can be tested using the following assays todemonstrate their prostanoid antagonist or agonist activity in vitro andin vivo and their selectivity. The prostaglandin receptors investigatedare DP, EP₁, EP₂, EP₃, EP₄, FP, IP and TP.

The ability of compounds to antagonise EP₁ & EP₃ receptors may bedemonstrated using a functional calcium mobilisation assay. Briefly, theantagonist properties of compounds are assessed by their ability toinhibit the mobilisation of intracellular calcium ([Ca²⁺]_(i)) inresponse to activation of EP₁ or EP₃ receptors by the natural agonisthormone prostaglandin E₂ (PGE₂). Increasing concentrations of antagonistreduce the amount of calcium that a given concentration of PGE₂ canmobilise. The net effect is to displace the PGE₂ concentration-effectcurve to higher concentrations of PGE₂. The amount of calcium producedis assessed using a calcium-sensitive fluorescent dye such as Fluo-3, AMand a suitable instrument such as a Fluorimetric Imaging Plate Reader(FLIPR). Increasing amounts of [Ca²⁺]_(i) produced by receptoractivation increase the amount of fluorescence produced by the dye andgive rise to an increasing signal. The signal may be detected using theFLIPR instrument and the data generated may be analysed with suitablecurve-fitting software.

The human EP₁ or EP₃ calcium mobilisation assay (hereafter referred toas ‘the calcium assay’) utilises Chinese hamster ovary-K1 (CHO-K1) cellsinto which a stable vector containing either EP₁ or EP₃ cDNA haspreviously been transfected. Cells are cultured in suitable flaskscontaining culture medium such as DMEM:F-12 supplemented with 10% v/vfoetal calf serum, 2 mM L-glutamine, 0.25 mg/ml geneticin and 10 □g/mlpuromycin.

For assay, cells are harvested using a proprietary reagent thatdislodges cells such as Versene. Cells are re-suspended in a suitablequantity of fresh culture media for introduction into a 384-well plate.Following incubation for 24 hours at 37° C. the culture media isreplaced with a medium containing fluo-3 and the detergent pluronicacid, and a further incubation takes place. Concentrations of compoundsare then added to the plate in order to construct concentration-effectcurves. This may be performed on the FLIPR in order to assess theagonist properties of the compounds. Concentrations of PGE₂ are thenadded to the plate in order to assess the antagonist properties of thecompounds.

The data so generated may be analysed by means of a computerisedcurve-fitting routine. The concentration of compound that elicits ahalf-maximal inhibition of the calcium mobilisation induced by PGE₂(pIC₅₀) may then be estimated.

By application of this technique, compounds of the examples had anantagonist pIC₅₀ value of between 7.0 and 9.5 at EP₁ receptors and pIC₅₀value of <6.0 at EP₃ receptors. Preferred compounds have an antagonistpIC₅₀ value of greater than 8.0 at EP₁ receptors.

No toxicological effects are indicated/expected when a compound (of theinvention) is administered in the above mentioned dosage range.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation the following claims:

1. A compound of formula (I):

wherein: A is an optionally substituted phenyl, or an optionallysubstituted 5- or 6-membered heterocyclyl ring, or an optionallysubstituted bicyclic heterocyclyl group; R¹ is CO₂R⁴, CONR⁵R⁶, CH₂CO₂R⁴,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted SO₂alkyl, SO₂NR⁵R⁶, NR⁵CONR⁵R⁶, CONR⁵R⁶,2H-tetrazol-5-yl-methyl or optionally substituted heterocyclyl; each R²is independently halo, optionally substituted alkyl, CN, SO₂R⁵, SR⁵,NO₂, optionally substituted aryl, CONR⁵R⁶ or optionally substitutedheteroaryl; R^(x) is optionally substituted alkyl wherein 1 or 2 of thenon-terminal carbon atoms may optionally be replaced by a groupindependently selected from NR⁴, O or SO_(n), wherein n is 0, 1 or 2: orR^(x) may be optionally substituted CQ₂-heterocyclyl or optionallysubstituted CQ₂-phenyl wherein Q is independently selected from hydrogenand CH₃; R⁴ is hydrogen or an optionally substituted alkyl; R⁵ ishydrogen or an optionally substituted alkyl; R⁶ is hydrogen or anoptionally substituted alkyl, optionally substituted SO₂aryl, optionallysubstituted SO₂heterocyclyl group, CN, optionally substituted CH₂aryl orCOR⁷; R⁷ is hydrogen, optionally substituted heteroaryl or optionallysubstituted aryl; R⁸ and R⁹ independently is hydrogen or alkyl; and n isan integer from 0 to 2; wherein when A is a 6-membered ring the R¹ andcyclopentene group are attached to carbon atoms 1,2-, 1,3- or1,4-relative to each other, and when A is a five-membered ring orbicyclic heterocyclyl group the R¹ and cyclopentene group are attachedto substitutable carbon atoms 1,2- or 1,3-relative to each other; or apharmaceutically acceptable derivative thereof.
 2. A compound accordingto claim 1 wherein A is selected from phenyl, pyridyl, pyridazinyl,pyrazinyl and pyrimidinyl, all of which may be optionally substituted.3. A compound according to claim 1 wherein R¹ represents CO₂R⁴. whereinR⁴ is hydrogen or C₁₋₄alkyl.
 4. A compound according to claim 1 whereinA is a six membered ring and R¹ is attached to the group A in the 3position relative to the bond attaching A to the cyclopentene ring.
 5. Acompound according to claim 1 which is a compound of formula (II):

wherein: R¹ is CO₂R⁴; R² is halo, optionally substituted C₁₋₆alkyl, CN,SC₁₋₆alkyl, or SO₂C₁₋₆alkyl; each R³ is independently halo, optionallysubstituted OC₁₋₆alkyl, or optionally substituted C₁₋₆alkyl; m is aninteger from 0 to 3; n is an integer from 0 to 2; W, X, Y and Z are eachCR¹² or N wherein at least two of W, X, Y or Z is CR¹²; and when each ofW, X, Y, and Z is CR¹² then each R¹² is independently selected fromhydrogen, halogen, NR⁵R⁶, NHCOC₁₋₆alkyl, NHSO₂C₁₋₆alkyl, C₁₋₆alkyl andNR¹⁰R¹¹, and when at least one of W, X, Y and Z is N then each R¹² isselected from hydrogen and NH₂; or a pharmaceutically acceptablederivative thereof.
 6. A compound selected from:{2-[5-chloro-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic acid;3-{2-[2-(benzyloxy)-phenyl]-cyclopent-1-enyl]-benzoic acid;3-{2-[5-bromo-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic acid;3-{2-[5-bromo-2-(4-Chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid;3-{2-[5-bromo-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid;3-{2-[5-bromo-2-(3,4-dichlorobenzyloxy)-penyl]-cyclopent-1-enyl}-benzoicacid;3-{2-[5-bromo-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid;3-{2-[5-bromo-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid;3-{2-[5-bromo-2-(4-methoxybenzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid;5-{2-[5-chloro-2-(4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid; 5-{2-[5-chloro-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-chloro-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-chloro-2-(3,4-dichlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-chloro-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-chloro-2-(4-methoxybenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid; 5-{2-[5-bromo-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-bromo-2-(4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-bromo-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-bromo-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-bromo-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-bromo-2-(4-methoxybenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-bromo-2-(cyclohexylmethoxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-trifluoromethyl-2-(4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-trifluoromethyl-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinicacid;5-{2-[5-trifluoromethyl-2-(cyclohexylmethoxy)-phenyl]-cyclopent-1-enyl]-nicotinicacid;6-{2-[5-chloro-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylicacid;6-{2-[5-chloro-2-(4-chloro-2-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylicacid;6-{2-[5-chloro-2-(4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-pyridine2-carboxylic acid;6-{2-[5-chloro-2-(4-fluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-pyridine2-carboxylic acid;3-{2-[5-methylsulfonyl-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid;3-{2-[5-methylsulfonyl-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid;3-{2-[5-methylsulfonyl-2-(4-fluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid;3-{2-[5-methanesulfonyl-2-(4-fluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid;3-{2-[5-methylsulfonyl-2-(2,4-difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid;3-{2-[5-methanesulfonyl-2-(2,4-difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid; 3-{2-[2-(2,4-difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid;3-{2-[2-(4-chloro-2-fluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid; 3-{2-[2-(4-methoxy-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid; 3-{2-[5-cyano-2-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid;3-{2-[5-cyano-2-(2,4-difluoro-benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoicacid;2-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4-carboxylicacid;6-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;6-{2-[5-methyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;6-{2-[5-methyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;2-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-4-carboxylicacid;2-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-4-carboxylicacid;4-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;4-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;6-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-aminopyrazine-2-carboxylicacid;2-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4-carboxylicacid;2-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4-carboxylicacid;6-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicacid; 3-{2[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoicacid;6-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;6-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;6-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;3-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoicacid;3-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoicacid;3-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoicacid;3-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-acetamidobenzoicacid;3-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-acetamidobenzoicacid;3-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-acetamidobenzoicacid;3-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicacid;3-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicacid;3-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicacid;3-{2-[5-bromo-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicacid;3-{2-[5-bromo-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicacid;3-{2-[5-bromo-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-propionamidobenzoicacid;5-{2-[trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}nicotinicacid N-oxide;5-{2-[5-fluoro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(propionamido)benzoicacid;5-{2-[5-methyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(propionamido)benzoicacid;5-{2-[5-methyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(propionamido)benzoicacid; 5-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-2-methylbenzoicacid;5-[2-(2-Benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-propionylaminobenzoicacid;2-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}isonicotinicacid;2-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}isonicotinicacid; 2-{2-[5-chloro-2-benzyloxyphenyl]cyclopent-1-enyl}isonicotinicacid;2-{2-[5-bromo-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}isonicotinicacid;5-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-3-propionylaminobenzoicacid;5-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-3-isobutyrylaminobenzoicacid;5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-pyrrolidin-1-yl)benzoicacid;5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-pyrrolidin-1-yl)benzoicacid;5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-pyrrolidin-1-yl)benzoicacid;5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-piperidin-1-yl)benzoicacid;5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-piperidin-1-yl)benzoicacid;5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxo-piperidin-1-yl)benzoicacid;6-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicacid;6-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicacid;6-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicacid;5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoicacid;5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoicacid;5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoicacid;5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoicacid;5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-aminobenzoicacid;5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoicacid;5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoicacid;5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoicacid;5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoic acid;5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-acetamidobenzoicacid5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-acetamidobenzoicacid;5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-acetamidobenzoicacid;5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-acetamidobenzoicacid;5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-acetamidobenzoicacid;5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopenten-1-enyl}-3-acetamidobenzoicacid;5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(morpholin-4-yl)benzoicacid;5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(morpholin-4-yl)benzoicacid;5-{2-[5-chloro-2-(−4-fluorobenzyloxy)phenyl]cyclopenten-1-enyl}-3-(morpholin-4-yl)benzoicacid;5-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methylaminobenzoicacid;5-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methylaminobenzoicacid;5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-methylaminobenzoicacid;2{2-[5-trifluoromethyl-2-(2,4-diflurobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-4-carboxylicacid;2{2-[5-bromo-2-(2,4-diflurobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-4-carboxylicacid;2{2-[5-bromo-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-4-carboxylicacid;2-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-5-amino-6-carboxylicacid;2-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-aminopyrazine-6-carboxylicacid;3-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicacid;3-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicacid;6-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicacid;5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(morpholin-4-yl)benzoicacid;5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopenten-1-enyl}-3-morpholin-4-ylbenzoicacid;5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopenten-1-enyl}-3-(morpholin-4-yl)benzoicacid;5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoicacid;5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-methanesulphonylaminobenzoic acid;5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-diethylaminobenzoicacid;6-{2-[5-methyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicacid;6-{2-[5-methyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylicacid;6-{2-[5-fluoro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;6-{2-[5-fluoro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;6-{2-[5-fluoro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;6-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridazine-4-carboxylicacid;6-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridazine-4-carboxylicacid;6-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridazine-4-carboxylicacid;5-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-2-methylbenzoicacid;5-[2-(2-(4-fluorobenzyloxy)-5-chlorophenyl)cyclopent-1-enyl]-2-methylbenzoicacid;5-[2-(2-(4-fluorobenzyloxy)-5-chlorophenyl)cyclopent-1-enyl]-2-fluorobenzoicacid;5-[2-(2-benzyloxy)-5-chlorophenyl)cyclopent-1-enyl]-2-fluorobenzoicacid;5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}nicotinicacid; 4-{2-[2-(benzyloxy)phenyl]cyclopent-1-enyl}-benzoic acid;4-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-benzoic acid;3-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicacid;3-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicacid;3-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicacid;3-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-methylbenzoicacid;3-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoicacid;3-{2-[5-chloro-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoicacid;3-{2-[5-chloro-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoicacid;3-{2-[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoicacid;3-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-fluorobenzoicacid;2-{2-[5-bromo-2-(4-fluorobenzyloxy)phenyl]-cyclopent-1-enyl}-isonicotinicacid; 2-{2-[2-(4-fluorobenzyloxy)phenyl]-cyclopent-1-enyl}-isonicotinicacid;6-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;6-{2-[5-chloro-2-(4-bromobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;6-{2-[5-chloro-2-(2-chloro-4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;6-{2-[5-chloro-2-(2,4,6-trifluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;6-{2-[5-chloro-2-(2,6-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;6-{2-[5-chloro-2-(2-fluoro-4-trifluoromethylbenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;6-{2-[5-chloro-2-(3,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;6-{2-[5-chloro-2-(2,3-difluorobenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid sodium salt;6-{2-[5-chloro-2-(4-methylbenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid sodium salt;6-{2-[5-chloro-2-(4-trifluoromethylbenzyloxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylicacid;3-{2[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-5-aminobenzoicacid;2-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}pyrimidine-4-carboxylicacid;5-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-2-acetamidobenzoicacid;3-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-fluorobenzoicacid;5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-2-methylbenzoicacid;5-{2-[5-chloro-2-(2,4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopyrrolidin-1-yl)benzoicacid;5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopyrrolidin-1-yl)benzoicacid;5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopyrrolidin-1-yl)benzoicacid;5-{2-[5-chloro-2-(2,4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopiperidin-1-yl)benzoicacid;5-{2-[5-chloro-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopiperidin-1-yl)benzoicacid; and5-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-3-(2-oxopiperidin-1-yl)benzoicacid and pharmaceutically acceptable derivatives thereof.
 7. Apharmaceutical composition comprising a compound according to claim 1together with a pharmaceutical carrier and/or excipient. 8-9. (canceled)10. A method of treating a human or animal subject suffering from acondition which is mediated by the action of PGE₂ at EP₁ receptors whichcomprises administering to said subject an effective amount of acompound according to claim
 1. 11. A method of treating a human oranimal subject suffering from a pain, inflammatory, immunological, bone,neurodegenerative or renal disorder, which method comprisesadministering to said subject an effective amount of a compoundaccording to claim
 1. 12. A method of treating a human or animal subjectsuffering from inflammatory pain, neuropathic pain or visceral painwhich method comprises administering to said subject an effective amountof a compound according to claim
 1. 13-16. (canceled)
 17. The compoundaccording to claim 5, wherein R¹ is CO₂R⁴; R² is halo, C₁₋₄alkyl, CF₃,CN, SC₁₋₆alkyl, or SO₂C₁₋₆alkyl; each R³ is independently halo,optionally substituted OC₁₋₆alkyl, or optionally substituted C₁₋₆alkyl;m is an integer from 0 to 3; n is an integer from 0 to 2; W, X, Y and Zare each CR¹² or N wherein at least two of W, X, Y or Z is CR¹²; andwhen each of W, X, Y, and Z is CR¹² then each R¹² is independentlyselected from hydrogen, halogen, NR⁵R⁶, NHCOC₁₋₆alkyl, NHSO₂C₁₋₆alkyl,C₁₋₆alkyl and NR¹⁰R¹¹, and when at least one of W, X, Y and Z is N theneach R¹² is selected from hydrogen and NH₂; or a pharmaceuticallyacceptable derivative thereof.
 18. A method of treating a human oranimal subject suffering from pain associated with migraine which methodcomprises administering to said subject an effective amount of acompound according to claim
 1. 19.6-{2-[5-Chloro-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylicacid or a pharmaceutically acceptable derivative thereof.
 20. Apharmaceutical composition comprising the compound according to claim 19together with a pharmaceutical carrier and/or excipient.
 21. A method oftreating a human or animal subject suffering from a condition which ismediated by the action of PGE₂ at EP₁ receptors which comprisesadministering to said subject an effective amount of a compoundaccording to claim
 19. 22. A method of treating a human or animalsubject suffering from a pain, inflammatory, immunological, bone,neurodegenerative or renal disorder, which method comprisesadministering to said subject an effective amount of a compoundaccording to claim
 19. 23. A method of treating a human or animalsubject suffering from inflammatory pain, neuropathic pain or visceralpain which method comprises administering to said subject an effectiveamount of a compound according to claim
 19. 24. A method of treating ahuman or animal subject suffering from pain associated with migrainewhich method comprises administering to said subject an effective amountof a compound according to claim
 19. 25.6-{2-[5-Chloro-2-(2,4-difluorobenzyloxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylicacid.